ABCMdb

ABCC6 p.Arg1141*

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Publications

PMID: 18220559 [PubMed] Yu XQ et al: "Multidrug resistance associated proteins as determining factors of pharmacokinetics and pharmacodynamics of drugs."

No. Sentence Comment

406 MRP Chromosomal location Amino acid variation Nucleotide variation Location References Lys13Asn G39GC Exon1 His68Tyr C202T Exon2 Ser346Phe C1037T Exon9 Gln513Lys C1537A Exon12 Arg1297His G3890A Exon27 MRP3 17q21.3 Gly1423Arg G4267A Exon29 [241] MRP4 13q32.1 Unknown MRP5 3q27 Unknown L63L W64R 189G>C 190T>C Exon2 Exon2 [250] T364R Q378X 1091C>G 1132C>T Exon9 Exon9 [260, 261] R518X R518Q 1552 C>T 1553G>A Exon12 Exon12 [247, 262] R1141X R1138Q T1130M R1114C M1127T 3421C>T 3413G>A 3389C>T 3340C>T 3380C>T Exon24 Exon24 Exon24 Exon24 Exon24 [246, 247] R1275X 3823C>T Exon27 [246] P1346S 4036C>T Exon28 [246] MRP6 16p13.1 E1400K 4198G>A Exon29 [247] MRP7 6p12-21 Unknown MRP8 16q12.1 Unknown MRP9 16q12.1 Unknown CONCLUSIONS AND FUTURE DIRECTIONS MRPs which belong to the ABC transporter family are able to transport a remarkable array of diverse endo- and xenobiotics and their metabolites. Login to comment

PMID: 10811882 [PubMed] Ringpfeil F et al: "Pseudoxanthoma elasticum: mutations in the MRP6 gene encoding a transmembrane ATP-binding cassette (ABC) transporter."

No. Sentence Comment

74 The mutation in exon 24 resulted in substitution of a codon for arginine by a stop codon, a mutation designated R1141X. Login to comment
77 MRP6 mutations in families with PXE Family Age and sex of proband Mutation Exon Consequence Verification* 1 53 F 3421C 3 T 24 R1141X BsiYI 3803G 3 A 27 R1268Q BstXI 2 29 F 3412C 3 T 24 R1138W MspI 3 40 F 3421C 3 T 24 R1141X BsiYI Partial deletion 24† Allelic loss D16S2720 MRP6 D16B9622 4 53 F 3736-1G 3 A 27 Altered splicing of exon 27 AciI Partial deletion 27† Allelic loss D16S2720 MRP6 D16B9622 5 60 M 3413G 3 A 24 R1138Q MspI 3803G 3 A 27 R1268Q BstXI 6 28 F 3421C 3 T 24 R1141X BsiYI 7 41 M 3803G 3 A 27 R1268Q BstXI 8 25 F 3421C 3 T 24 R1141X BsiYI *Mutations were verified in the proband and his/her family members by digestion with restriction enzyme, or in case of deletion, by microsatellite markers indicated. Login to comment
98 Examination of the proband`s DNA by CSGE and nucleotide sequencing (Fig. 2 A and B) revealed a homozygous mutation in exon 24, 3421C3T, which resulted in a premature termination codon R1141X. Login to comment
101 Examination of the parents revealed that the father (I-2) was heterozygous for the mutation R1141X. Login to comment
111 These findings are consistent with the interpretation that the proband and her sister had inherited a nonsense mutation from the father and a deletion mutation affecting exon 24 of MRP6 from the mother, thus reducing the paternal mutation R1141X to hemizygosity. Login to comment
113 A search for other mutations in the MRP6 gene was unyielding, and he may therefore manifest with mild features of PXE, reflecting his carrier status for the mutation R1141X. Login to comment
142 Evaluation of their DNA revealed that the patient in family 5 was compound heterozygous for nucleotide substitutions 3413G3A and 3803G3A in exons 24 and 27, which resulted in the amino acid substitutions R1138Q and R1268Q, respectively. In families 6-8, heterozygous nucleotide substitutions were discovered, resulting in the mutations R1141X (families 6 and 8), and R1268Q (family 7). Login to comment
159 Although only one mutation in each of the latter three individuals was observed, it is likely that PXE in these cases was also autosomal recessive, because each of the two distinct mutations (R1141X and R1268Q) discovered in these three probands were also present in the multiplex families, and the heterozygous carriers did not show definitive signs of the disease. Login to comment

PMID: 10913334 [PubMed] Germain DP et al: "Homozygosity for the R1268Q mutation in MRP6, the pseudoxanthoma elasticum gene, is not disease-causing."

No. Sentence Comment

4 In one large PXE pedigree for which we had identified a nonsense mutation (R1141X), we came across a G to A transition at position 3803 of the MRP6 cDNA sequence (R1268Q). Login to comment
18 During our molecular analysis of the MRP6 gene in PXE patients, we came across a G to A transition at position 3803 of the cDNA sequence, altering the codon (CGG) for arginine to the codon (CAG) for glutamine (R1268Q) in a pedigree in which we had previously identified a nonsense mutation (R1141X). Login to comment
49 During our mutational analysis, we found a heterozygous C to T transition at cDNA position 3421 of the MRP6 gene, predicting termination of translation at codon 1141 (R1141X) (Fig. 2). Login to comment
75 Detection of the R1141X nonsense mutation by direct sequencing of the MRP6 gene in the proband. Login to comment

PMID: 10951257 [PubMed] Ringpfeil F et al: "Abstracts: mutations in the MRP6 gene cause pseudoxanthoma elasticum"

No. Sentence Comment

8 A particular stop codon mutation, R1141X, occurred independently in six unrelated kindreds. Login to comment

PMID: 11179012 [PubMed] Ringpfeil F et al: "Compound heterozygosity for a recurrent 16.5-kb Alu-mediated deletion mutation and single-base-pair substitutions in the ABCC6 gene results in pseudoxanthoma elasticum."

No. Sentence Comment

24 OF AFFECTED FAMILY MEMBERS COMPLEMENTARY MUTATION PHENOTYPE a When Studied At Disease Onset 1 (German) 61 9 2 R1164X Skin-cobblestoning on neck, antecubital fossae, and wrists, sagging skin in axillae and bilateral groin; eyes-angioid streaks, central vision loss; CVS-claudication, ischemic attack; other-ovarian cancer 2 (British) 60 Unknown 3 R1164X Skin-moderate to severe involvement; eyes-loss of vision 3 (British) 41 Unknown 3 R1141X Skin-cobblestoning on neck, axillae, and bilateral groin; eyes-angioid streaks; CVS-coronary artery disease, GI bleeding 4 (Greek) 60 51 2 3736-1GrA Skin-cobblestoning in axillae, bilateral groin, and antecubital fossae; eyes-angioid streaks, central vision loss, macular degeneration; CVS-angina, abdominal pain, loss of peripheral pulses; other-depression, chronic fatigue syndrome a CVS p cardiovascular system; GI p gastrointestinal. Login to comment
56 Clinical Assessment of Families with PXE Members of families 1, 3, and 4 were personally examined at least by one of the authors; information on Table 2 Haplotypes of Affected Individuals in Four Unrelated Families with PXE MARKER a HAPLOTYPE FOR b del/R1164X del/R1141X; Family 3 del/3736-1GrA; Family 4Family 1 Family 2 D16S3114 4 4 10 5 9 6 9 4 D16S500 6 3 4 10 4 8 6 10 D16S2619 2 1 3 2 2 3 2 2 D16S3079 2 3 2 3 1 9 8 7 D16S3060 4 2 8 2 7 4 5 8 D16S405 8 3 4 3 4 8 3 4 D16B9622 2 2 2 2 1 2 3 1 D16S764 4 2 3 2 2 2 3 2 D16S79 8 0 3 3 3 3 3 2 D16S3103 7 1 3 1 9 3 7 4 D16S3017 3 2 4 1 5 4 2 4 D16S499 1 5 5 1 8 7 5 8 D16S3036 8 8 7 7 8 11 4 6 a The distances between the listed markers are as follows: telomere, D16S3114 (1.9 cM) D16S500 (0.5 cM) D16S2619 (0.7 cM) D16S3079 (0.5 cM) D16S3060 (22 kb) D16S405 (430 kb) D16B9622 (0.7 kb) ABCC6 (317 kb) D16S764 (8 kb) D16S79 (1.5 cM) D16S3103 (0.4 cM) D16S3017 (0.9 cM) D16S499 (1.5 cM) D16S3036, centromere. Login to comment
99 In these families, designated here as "family 3" (family 3 in Ringpfeil et al. 2000) and "family 4" (family 4 in Ringpfeil et al. 2000), a nonsense mutation (R1141X) and a splicing mutation (3736-1GrA) are located in exon 24 and in the 3 acceptor splice site of intron 26, respectively. Login to comment
154 In each family, the proband was initially shown to be apparently homozygous for a nucleotide substitution, resulting in either a nonsense mutation (R1164X, R1164X, and R1141X in families 1, 2, and 3, respectively) or a splice-site mutation (3736-1GrA in family 4). Login to comment
180 Exon 24 encodes a segment of MRP6 residing within TMSD3, and the mutations R1141X and R1164X are predicted to result in the synthesis of a truncated polypeptide entirely devoid of NBF2 (fig. 4A). Login to comment

PMID: 11427982 [PubMed] Uitto J et al: "Molecular genetics of pseudoxanthoma elasticum: a metabolic disorder at the environment-genome interface?"

No. Sentence Comment

68 A particularly common mutation appears to be R1141X, which has been independently described in families of various ethnic backgrounds10-13,17. Login to comment
75 Thisraisesthequestionoftherelationshipbetweenthe MRP6mutationsandthemanifestationsinPXE affectingtheelasticfibersinvariousorgans.Itmaywell Opinion CR1339C G1345R TRENDS in Molecular Medicine 10 kb NBF2NBF1 0.5 kb Extracellular Intracellular GS 5' 3' R1138Q R1164X R1141X R1138W 2787+1G T A455P R518Q R1114P R1314W (a) (b) (c) EcoRI SmaI SmaI SmaI SacI SacI SmaI N GS 2542delG 1944del22 4220insAGAA 3775delT 3736-1G A Fig. 3. Login to comment

PMID: 11493310 [PubMed] Ringpfeil F et al: "Molecular genetics of pseudoxanthoma elasticum."

No. Sentence Comment

74 Three recurrent mutations, R1141X, R1164X, and Del exon 23-29, are boxed (see text). Login to comment
87 Among the PTC causing mutations, two recurrent nonsense mutations, R1141X and R1164X, have been identified Figure . Login to comment
93 In particular, the R1141X mutation, which results from C»T transition in nucleotide position 3421, has been encountered in approximately 15% of the mutated alleles disclosed thus far. Login to comment

PMID: 11536079 [PubMed] Le Saux O et al: "A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum."

No. Sentence Comment

8 R1141X was found in our patient cohort at a frequency of 18.8% and was preponderant in European patients. Login to comment
9 ABCC6del23-29 occurred at a frequency of 12.9% and was prevalent in patients from the United States. These results suggested that R1141X and ABCC6del23-29 might have been derived regionally from founder alleles. Login to comment
85 PXE Mutations The most-prevalent mutations detected in the ABCC6 gene were missense substitutions (21 [58.3%] mutations, Table 1 ABCC6 Mutations in a Cohort of Patients with PXE CHANGE IN STATUS a ORIGIN(S)b EXON(S)c REFERENCE(S)Amino Acid Nucleotide … 179-195del ht Belgium 2 Present study … 938-939insT ch, ht SA, UK 8 Present study N411K 1233TrG ht US 10 Present study A455P 1363GrC Nd Nd 11 Uitto et al. (2001) R518Q 1553GrA ch, ht Belgium 12 Present study, Uitto et al. (2001) F568S 1703TrC ch US 13 Present study … ABCC6del15 hm SA 15 Present study … 1944del22 ht Holland 16 Bergen et al. (2000) … 1995delG ht Germany 16 Present study L673P 2018TrC ch SA 16 Present study R765Q 2294GrA ht Germany 18 Present study Y768X 2304CrA ch, ht SA 18 Present study … 2322delC ht US 18 Present study … 2542delG Nd Nd 19 Uitto et al. (2001) … IVS21ϩ1GrT ch US, Germany i-21 Present study, Uitto et al. (2001) R1030X 3088CrT ht SA, UK 23 Present study R1114P 3341GrC hm UK 24 Present study S1121W 3362CrG ch Germany 24 Present study R1138W 3412CrT hm Nd 24 Ringpfeil et al. (2000) R1138P 3413GrC ch Germany 24 Present study R1138Q 3413GrA ch UK, US 24 Present study, Ringpfeil et al. (2000) R1141X 3421CrT All All 24 Present study and othersd R1164X 3490CrT ch Germany, UK 24 Ringpfeil et al. (2001) G1203D 3608GrA ch Germany 25 Present study … IVS26-1GrA ch Belgium i-26 Present study, Ringpfeil et al. (2000, 2001) Q1237X 3709CrT ch Belgium 26 Present study … 3775delT ht, hm SA, US, Holland 27 Present study, Bergen et al. (2000) V1298F 3892GrT ht US 28 Present study T1301I 3902CrT ch Belgium 28 Present study G1302R 3904GrA hm US 28 Present study A1303P 3907GrC ch Belgium 28 Present study R1314W 3940CrT hm US 28 Present study R1314Q 3941GrA ch Germany 28 Present study G1321S 3961GrA ht US 28 Present study R1339C 4015CrT All SA, US 28 Present study, Struk et al. (2000) Q1347H 4041GrC hm US 28 Present study D1361N 4081GrA ch Germany 29 Present study … 4104delC ch Belgium 29 Present study R1398X 4192CrT ch Belgium 29 Present study … ABCC6del23-29 ch US 23-29 Present study, Ringpfeil et al. (2001) … 4220insAGAA ht Holland 30 Bergen et al. (2000) I1424T 4271TrC ht US 30 Present study … ABCC6del ht Holland all Bergen et al. (2000) a Nd p not determined; hm p homozygote; ht p heterozygote; ch p compound heterozygote. Login to comment
94 Although most of the mutations reported here appear to be unique, a few disease-causing variants have been found to occur frequently in apparently unrelated individuals; R1141X was found at Table 2 Frequencies of Mutant Alleles Found in a Cohort of 101 Unrelated Patients with PXE MUTATION a OVERALL EUROPE UNITED STATES No. of Alleles Frequency (%) No. of Alleles Frequency (%) No. of Alleles Frequency (%) R1141X 38 18.8 33 28.4 3 4.1 ABCC6del23-29 26 12.9 5 4.3 21 28.4 IVS21ϩ1GrT 7 3.5 4 3.4 3 4.1 G1302R 4 2.0 0 .0 4 5.4 A1303P 4 2.0 3 2.6 1 1.4 R1314W 3 1.5 0 .0 3 4.1 R518Q* 3 1.5 1 .9 1 1.4 3775delT* 3 1.5 2 1.7 0 .0 R1138Q 2 1.0 1 .9 1 1.4 V1298F 2 1.0 0 .0 2 2.7 R1339C 2 1.0 0 .0 2 2.7 Q1347H 2 1.0 0 .0 2 2.7 4104delC* 2 1.0 1 .9 0 .0 179-195del 1 .5 1 .9 0 .0 938-939insT* 1 .5 0 .0 0 .0 N411K 1 .5 0 .0 1 1.4 F568S 1 .5 0 .0 1 1.4 1995delG 1 .5 1 .9 0 .0 R765Q 1 .5 1 .9 0 .0 2322delC 1 .5 0 .0 1 1.4 R1030X* 1 .5 0 .0 0 .0 R1114P 1 .5 1 .9 0 .0 S1121W 1 .5 1 .9 0 .0 R1138P 1 .5 1 .9 0 .0 G1203D 1 .5 1 .9 0 .0 IVS26-1GrA 1 .5 1 .9 0 .0 Q1237X 1 .5 1 .9 0 .0 W1241C 1 .5 1 .9 0 .0 T1301I 1 .5 1 .9 0 .0 R1314Q 1 .5 1 .9 0 .0 D1361N 1 .5 1 .9 0 .0 R1398X 1 .5 1 .9 0 .0 G1321S 1 .5 0 .0 1 1.4 I1424T 1 .5 0 .0 1 1.4 ? Login to comment
102 Interestingly, alleles R1141X and ABCC6del23-29 were found to occur at different frequencies when patient origin was considered. Login to comment
103 R1141X was far more frequently represented in the European cohort (33 [28.4%] of 116 alleles) than in the U.S. cohort of patients with PXE (3 [4.1%] of 74). Login to comment
105 Indeed, 15 of 26 Belgians, 8 of 15 Germans, 3 of 12 British, 2 of 6 Dutch, and 1 of 1 Italian carried an R1141X allele in a homozygous, compound heterozygous, or heterozygous state. Login to comment
106 In the U.S. cohorts, three patients carried a single R1141X allele. Login to comment
107 Among the South African patients, 2 of the 5 who were of British ancestry had the nonsense mutation in the heterozygous or compound heterozygous state, and 2 of the 17 of the Afrikaner patients carried a heterozygous or compound heterozygous R1141X. Login to comment
121 The frequency of individuals homozygous for these two frequently occurring disease-causing alleles (R1141X and ABCC6del23-29) was observed to be in Hardy-Weinberg equilibrium in the European and United States cohorts, respectively. Login to comment
139 One nonsense mutation (R1141X) that we have previously characterized in a homozygous state was indeed associated with no detectable ABCC6 messenger in RNA samples obtained from skin fibroblasts (Le Saux et al. 2000), and the absence of any ABCC6 mRNA is probably caused by NMD and would result in a null allele. Login to comment
157 Characterization of Two Alu-Mediated Deletions ABCC6del23-29.-A loss of heterozygosity of an R1141X allele was detected in three affected children of a two-generation family from the United States. These affected individuals seemed homozygous for R1141X; whereas the mother appeared to be heterozygous for this allele, and the father appeared to have two normal alleles. Login to comment
159 These results suggested that the affected offspring in this family had inherited a single maternal R1141X mutation and a paternally derived deletion involving exon 24, thereby reducing the nonsense mutation to hemizygosity in all three patients. Login to comment
213 Among the four Belgian patients with homozygous R1141X alleles, three had typical skin lesions, and all patients displayed moderate-to- severe ocular involvement. Login to comment
228 Although most mutations observed in ABCC6 were unique, two variants (R1141X and ABCC6del23-29) occurred at a high frequency (table 2). Login to comment
230 However, when patient ancestries were considered, R1141X was found to occur at a greater frequency in Europe, whereas ABCC6del23-29 was preponderant in the United States (table 2). Login to comment
236 A similar hypothesis could explain the high frequency of R1141X alleles in the European sample. Login to comment
237 However, to demonstrate that the various R1141X and ABCC6del23-29 alleles are identical by descent, the analysis of additional microsatellite markers and single-nucleotide polymorphisms within and in close proximity to ABCC6 will be required. Login to comment

PMID: 11702217 [PubMed] Pulkkinen L et al: "Identification of ABCC6 pseudogenes on human chromosome 16p: implications for mutation detection in pseudoxanthoma elasticum."

No. Sentence Comment

31 Specifically, NciI restriction enzyme was used for the detection of mutation 179del9, BstNI for the detection of mutation G1354R, and BsiYI for mutation R1141X. Login to comment
112 In addition to the missense mutation T364R, this patient was shown to have a recurrent nonsense mutation R1141X in exon 24 in the other ABCC6 allele, as shown by sequence analysis (Fig.4C). Login to comment
129 Screening of other parts of the gene revealed a recurrent nonsense mutation R1141X in exon 24 in the other allele of patient P2 (C). Login to comment
130 Thus, the patient is a compound heterozygote for mutations T364R/R1141X Table 3 Polymorphisms characterized in the region spanning 5`-UTR and exon 1 to intron 9 of ABCC6, as identified by the use of allele-specific primers aThe nucleotide positions refer to numbers in ABCC6 cDNA and are counted from the first nucleotide of the translation initiation codon ATG (Belinsky and Kruh 1999; GenBank accession nos. XM_007798, NM_001171) Location Nucleotide positiona Major allele Minor allele Allele frequences 5`-flanking 1-219 A C 0.950/0.050 5`-flanking 1-132 C T 0.953/0.047 5`-flanking 1-127 C T 0.857/0.143 Exon 3 232 G (Ala) T (Thr) - Intron 3 346-6 G A - Exon 6 645 G (Thr) A (Thr) - Intron 6 662+12 C T - Intron 6 662+114 T C 0.937/0.063 Intron 6 662+298 C G - Intron 6 662+305 T G - Intron 6 662+403 T A - Exon 7 793 A (Arg) G (Gly) 0.914/0.086 a number of duplicated regions (Doggett et al. 1995; Loftus et al. 1999; Cai et al. 2000). Login to comment
149 In this work, we have found three novel mutations, 179del9, T364R, and G1354R, and a recurrent nonsense mutation R1141X in two families with PXE (Fig.5). Login to comment
153 The proband in Family 2 is a compound heterozygote for R1141X and T364R mutations. Login to comment
154 The recurrent R1141X nonsense mutation predicts the elimination of the entire C-terminus from the protein, including part of the third transmembrane domain and the second nucleotide-binding fold (Fig.5). Login to comment

PMID: 12176944 [PubMed] Trip MD et al: "Frequent mutation in the ABCC6 gene (R1141X) is associated with a strong increase in the prevalence of coronary artery disease."

No. Sentence Comment

0 Feskens and Arthur A.B. Bergen Boer, Jacoline B. ten Brink, Aeilko H. Zwinderman, John J.P. Kastelein, Edith J.M. Mieke D. Trip, Yvo M. Smulders, Jurgen J. Wegman, Xiaofeng Hu, Jolanda M.A. Increase in the Prevalence of Coronary Artery Disease Frequent Mutation in the ABCC6 Gene (R1141X) Is Associated With a Strong ISSN: 1524-4539 Copyright (c) 2002 American Heart Association. Login to comment
7 Fax: Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, a division of Wolters http://circ.ahajournals.org//subscriptions/ Subscriptions: Information about subscribing to Circulation is online at at UNIV OF N CAROLINA CHAPEL HILL on August 8, 2011http://circ.ahajournals.org/Downloaded from Frequent Mutation in the ABCC6 Gene (R1141X) Is Associated With a Strong Increase in the Prevalence of Coronary Artery Disease Mieke D. Trip, MD; Yvo M. Smulders, MD, PhD; Jurgen J. Wegman, MD; Xiaofeng Hu, MD; Jolanda M.A. Boer, PhD; Jacoline B. ten Brink, Ing; Aeilko H. Zwinderman, PhD; John J.P. Kastelein, MD, PhD; Edith J.M. Feskens, PhD; Arthur A.B. Bergen, PhD Background-Pseudoxanthoma elasticum (PXE) is an inborn disorder of the connective tissue with specific skin, ocular, and cardiovascular disease (CVD) manifestations. Login to comment
9 In the Netherlands, as in the rest of Europe, a particular premature truncation variant ABCC6 (R1141X) was found in a large cohort of PXE patients. Login to comment
11 Methods and Results-To assess the relationship between the frequent R1141X mutation in the ABCC6 gene and the prevalence of premature coronary artery disease (CAD), we conducted a case-control study of 441 patients under the age of 50 years who had definite CAD and 1057 age-and sex-matched population-based controls who were free of coronary disease. Login to comment
12 Strikingly, the prevalence of the R1141X mutation was 4.2 times higher among patients than among controls (3.2% versus 0.8%; PϽ0.001). Login to comment
13 Consequently, among subjects with the R1141X mutation, the odds ratio for a coronary event was 4.23 (95% CI: 1.76 to 10.20, Pϭ0.001). Login to comment
14 Conclusion-The presence of the R1141X mutation in the ABCC6 gene is associated with a sharply increased risk of premature CAD. Login to comment
22 In parallel studies (Xiaofeng Hu, unpublished data), we found that the R1141X mutation is the most common mutation in Dutch PXE patients and families, and it seems as though this is the case for the rest of Europe as well. Login to comment
23 We therefore studied the prevalence of the R1141X mutation in the ABCC6 gene in patients with premature CAD and in a large population-based group of healthy controls to further delineate the role of this genetic variation as a risk factor for CAD. Login to comment
51 In cases, 14 of 441 (3.2%, 95% CI: 1.9 to 5.6) were carriers of the R1141X truncation variant, whereas 8 of 1057 controls (0.8%, 95% CI: 0.3 to 1.5) carried this ABCC6 mutation, yielding a statistically significant difference at a probability value Ͻ0.001 with an odds ratio corrected for age and sex of 4.23 (95% CI: 1.76 to 10.20). Login to comment
52 We subsequently categorized the premature CAD patients in carriers (nϭ14) and noncarriers (nϭ427) of the R1141X variant of the ABCC6 gene (Table 2). Login to comment
54 Discussion We demonstrate in a large case-control study that a strong association exists between a frequent mutation in the ABCC6 gene (R1141X) and the presence of premature CAD. Login to comment
64 Baseline Characteristics of Patients According to R1141X Genotype Variable Heterozygous nϭ14 Wild Type nϭ427 P Age, y 48.1Ϯ6.0 47.3Ϯ6.0 0.64 Male sex 10 (71) 322 (80) 0.43 Age at diagnosis 39.6Ϯ6.9 40.6Ϯ6.1 0.56 History of MI 11 (79) 312 (78) 0.93 Smoking 4 (29) 113 (28) 0.84 BMI, kg/m2 26.4Ϯ3.6 26.8Ϯ4.0 0.71 Hypertension 8 (57) 145 (36) 0.13 DM II 6 (43) 111 (27) 0.13 Family history CAD 9 (64) 229 (57) 0.33 Total cholesterol, mmol/L 5.96Ϯ1.36 5.81Ϯ1.60 0.73 HDL cholesterol, mmol/L 1.01Ϯ0.17 1.10Ϯ0.31 0.29 LDL cholesterol, mmol/L 3.96Ϯ1.27 3.82Ϯ1.53 0.74 Triglycerides, mmol/L 2.19Ϯ1.43 2.09Ϯ2.12 0.43 Values are meanϮSD or n (%). Login to comment

PMID: 12241726 [PubMed] Bradbury J et al: "Mutation affecting arterial elasticity associated with premature heart disease."

No. Sentence Comment

8 To find out, Trip and co-workers examined DNA samples from 441 patients younger than 50 years referred to an outpatient atherosclerosis clinic and from 1057 healthy controls for the R1141X mutation, "the most common ABCC6 mutation associated with PXE in the Netherlands", explains Trip. Login to comment
9 3·2% of patients had this mutation compared with only 0·8% of healthy controls, giving an odds ratio for coronary events among people with the R1141X mutation of 4·23 (95% CI 1·76-10·20; Circulation; published online Aug 5, 2002; DOI: 10.1161/01.CIR.0000028420.27813 .C0). Login to comment
10 "We are now looking at other mutations associated with PXE in the same population", says Trip, "and plan to extend our work on the R1141X mutation to other populations". Login to comment

PMID: 12384774 [PubMed] Le Saux O et al: "Evidence for a founder effect for pseudoxanthoma elasticum in the Afrikaner population of South Africa."

No. Sentence Comment

53 Two nonsense variants (Y768X and R1141X) and a single frameshift mutation (939insT) were also identified (Table 1). Login to comment
55 Two of the mutations found in the Afrikaner group, R1141X and 939insT, were also found in PXE individuals of British ancestries (Tables 1, 2). Login to comment
56 One of the latter individuals (from Family 212) carried the R1141X allele in association with 939insT. Login to comment
58 Moreover, two of the four R1141X alleles found in Afrikaner and British individuals occurred in similar haplotypes, also suggesting a possible consanguineous relationship between Family 206 (Afrikaner) and Family 216 (British ancestry). Login to comment
59 The remaining R1141X mutations, characterized in Family 224 (Afrikaner) and Family 212 (British ancestry) were found in different haplotypes indicating that 333 Table 1 ABCC6 mutations identified in a cohort of South African PXE patients of Afrikaner and other ancestries (nt nucleotide, aa amino acid, ni not identified, UK United Kingdom, Black black South Africans) Family Allele 1 Allele 2 Ancestry nt change aa change Exon Haplotype nt change aa change Exon Haplotype 201 4015C→T R1339C 28 I 4015C→T R1339C 28 I Afrikaner 203 4015C→T R1339C 28 I 3413G→A R1138Q 24 III Afrikaner 205 3413G→A R1138Q 24 III 2304C→A Y768X 18 II Afrikaner 206 4015C→T R1339C 28 I 3421C→T R1141X 24 Other Afrikaner 208 4015C→T R1339C 28 I 4015C→T R1339C 28 I Afrikaner 209 4015C→T R1339C 28 I 2018T→C L673P 16 Other Afrikaner 211 4015C→T R1339C 28 I 3413G→A R1138Q 24 III Afrikaner 222 4015C→T R1339C 28 I 4015C→T R1339C 28 I Afrikaner 223 4015C→T R1339C 28 I 2304C→A Y768X 18 II Afrikaner 225 4015C→T R1339C 28 I 4015C→T R1339C 28 I Afrikaner 226 4015C→T R1339C 28 I 2304C→A Y768X 18 II Afrikaner 228 4015C→T R1339C 28 I 2304C→A Y768X 18 II Afrikaner 229 4015C→T R1339C 28 I 4015C→T R1339C 28 I Afrikaner 213 939insT Frameshift 8 Other ni ni ni Other Afrikaner 214 4015C→T R1339C 28 I ni ni ni Other Afrikaner 224 3421C→T R1141X 24 Other ni ni ni Other Afrikaner 204 ni ni Other ni ni ni Other Afrikaner 212 3421C→T R1141X 24 Other 939insT Frameshift 8 Other UK 215 3775delT Frameshift 27 Other 4104delC Frameshift 29 Other UK 217 ABCC6del15 Frameshift 15 Other ABCC6del15 Frameshift 15 Other Indian 207 3088C→T R1030X 23 Other ni ni ni Other UK 216 3421C→T R1141X 24 Other ni ni ni Other UK 219 1553G→A R518Q 12 Other ni ni ni Other UK 221 ni ni Other ni ni ni Other Black Table 2 Frequencies of mutant ABCC6 alleles found in a cohort of PXE patients of Afrikaner and other ancestries (? Login to comment
60 unidentified alleles, MDR mutation detection rate) Mutation Overall Afrikaner ancestries Others ancestries Allele Allele Allele Allele Allele Allele count frequency (%) count frequency (%) count frequency (%) R1339C 18 37.5 18 52.9 0 0 Y768X 4 8.3 4 11.8 0 0 R1141X 4 8.3 2 5.9 2 14.3 R1138Q 3 6.3 3 8.8 0 0 939insT 2 4.2 1 2.9 1 7.1 ABCC6del15 2 4.2 0 0.0 2 14.3 L673P 1 2.1 1 2.9 0 0.0 R1030X 1 2.1 0 0.0 1 7.1 R518Q 1 2.1 0 0.0 1 7.1 3775delT 1 2.1 0 0.0 1 7.1 4104delC 1 2.1 0 0.0 1 7.1 ? Login to comment
83 All other mutated alleles, R1141X, L673P, 939insT and particularly the five unidentified mutations, were found in divergent haplotypes. Login to comment
84 The latter three alleles (R1141X, L673P and 939insT) could have been introduced by founder individuals or could represent de novo mutation events in the Afrikaner population. Login to comment

PMID: 12600949 [PubMed] Maccari F et al: "Anomalous structure of urinary glycosaminoglycans in patients with pseudoxanthoma elasticum."

No. Sentence Comment

154 Four of them were heterozygous for a stop codon mutation on one allele and a missense mutation on the other allele, one was heterozygous for a deletion on one allele and a nonsense mutation on the second allele, and five are still under investigation. The great majority of patients had the R1141X stop codon mutation in homozygosity or heterozygosity with another mutation. Login to comment

PMID: 12649085 [PubMed] Germain DP et al: "Arterial remodeling and stiffness in patients with pseudoxanthoma elasticum."

No. Sentence Comment

13 Vascular involvement is common, and patients with PXE typically present with arteriosclerosis, hypertension, transient ischemic attacks, and occlusive vascular changes at young ages.2 Cardiovascular complications, mainly coronary artery disease, are rare but can be life threatening.2 The estimated prevalence of PXE is 1 in 70 000 to 100 000.3 Although autosomal recessive inheritance (OMIM 264800) is most frequently found in PXE, autosomal dominant segregation (OMIM 177850) has also been proposed.4 The PXE locus has been mapped to chromosome 16p13.1, and mutations in the ABCC6 gene (previously known as MRP6 or eMOAT), encoding a 1503-amino acid putative membrane transporter of unknown function, have recently been simultaneously disclosed by 5 research groups as the genetic defect responsible for PXE.5-9 The existence of pseudogenes has been subsequently documented.10-13 The R1141X mutation in the ABCC6 gene is associated with a sharply increased risk of premature coronary artery disease.14 Histopathology of biopsies from clinically affected skin shows morphologically altered elastic fibers, which are fragmented and swollen and appear calcified when examined by special stains (eg, von Kossa), whereas PXE has also been characterized by proteoglycans accumulation, including heparan-sulfate and chondroitin-6-sulfate proteoglycans, glycosaminoglycan hyaluronic acid, decorin, and biglycan.15-17 Despite identification of the genetic defect, little is known about the pathogenesis of vascular lesions in PXE and the means for preventing arterial complications in young adults. Login to comment
29 Various mutations were identified, among which the nonsense R1141X was the most prevalent. Login to comment

PMID: 12673275 [PubMed] Hu X et al: "ABCC6/MRP6 mutations: further insight into the molecular pathology of pseudoxanthoma elasticum."

No. Sentence Comment

8 The R1141X mutation was by far the most common mutation identified in 19 (32.2%) patients. Login to comment
30 of patients Allele 1 Consequence Exon Allele 2 Consequence Exon Mode of inheritance in family 1 2247C>T Q749X 17 s 1 3421C>T R1141X 24 2247C>T Q749X 17 ar 9 3421C>T R1141X 24 ar,s, n 1 3421C>T R1141X 24 1944del22 Frameshift 16 n 3 3421C>T R1141X 24 Deletion A995del405 23-29 ar 1 3421C>T R1141X 24 4182delG Frameshift 29 ar 1 3421C>T R1141X 24 3775delT Frameshift 27 s 3 3421C>T R1141X 24 3421C>T R1141X 24 ar, s 1 2294G>A R765Q 18 3775delT Frameshift 27 ar 1 3341G>A R1114H 24 n 1 3390C>T T1130M 24 3390C>T T1130M 24 ar 1 3663C>T R1221C 26 3775delT Frameshift 27 n 1 3904G>C G1302R 28 s 1 3907G>A A1303P 28 Deletion A995del405 23-29 ar 1 4182G>T K1394N 29 Deletion A995del405 23-29 ar 1 4182delG Frameshift 29 n 1 4182delG Frameshift 29 4182delG Frameshift 29 ar 1 4377C>T R1459C 30 ad?, s,n 2 3775delT Frameshift 27 s,n 1 3775delT Frameshift 27 Deletion all? Login to comment
38 Table 2 Summary of ABCC6/MRP6 mutations associated with PXE known today: our data combined with those of the literature Mutation Protein alteration Nucleotide substitution Location Reference Nonsense Q378X 1132C > T Exon 9 19,20 R518X 1552C > T Exon 2 41 Q749X 2247C > T Exon 17 This study Y768X 2304C > A Exon 18 22 R1030X 3088C > T Exon 23 22 R1141X 3421C > T Exon 24 12,20,22,38,39, this study R1164X 3490C > T Exon 24 12,41 Q1237X 3709C > T Exon 26 22 R1398X 4192C >T Exon 29 22 T364R Missense N411K 1091C > G Exon 9 20 A455P 1233T > G Exon 10 22 R518Q 1363G > C Exon 11 38 F568S 1553G > A Exon 12 22,38 L673P 1703T > C Exon 13 22 R765Q 2018T > C Exon 16 22 R1114P 2294G > A Exon 18 22, this study R1114H 3341G > C Exon 24 22 S1121W 3341G > A Exon 24 This study T1130M 3362C > G Exon 24 22 R1138W 3390C > T Exon 24 This study R1138Q 3412C > T Exon 24 12 R1138P 3413G > A Exon 24 12,22 G1203D 3413G > C Exon 24 22 R1221C 3608G > A Exon 25 22 V1298F 3663C > T Exon 26 This study T1301I 3892G > T Exon 28 22 G1302R 3902C > T Exon 28 22 A1303P 3904G > A Exon 28 22, this study R1314W 3907G > C Exon 28 22, this study R1314Q 3940C > T Exon 28 22 G1321S 3941G > A Exon 28 22 R1339C 3961G > A Exon 28 22 Q1347H 4015C > T Exon 28 22,39 G1354R 4041G > C Exon 28 22 D1361N 4060G > C Exon 29 20,38 K1394N 4081G > A Exon 29 22 I1424T 4182G > T Exon 29 This study R1459C 4271T > C Exon 30 22 4377C > T Exon 30 This study Frameshift IVS17-12delT T Intron 17 This study IVS21+1G>T Intron 21 22,38 IVS26-1G>A Intron 26 12,21,22 179del 9 Exon 2 20 179-195del Exon 2 22 960del C Exon 8 41 1944del22 Exon 16 This study 1995delG Exon 16 22 2322delC Exon 18 22 2542delG Exon 19 41 3775delT Exon 27 This study 4104delC Exon 29 22 4182delG Exon 29 This study 938-939insT Exon 8 22 4220insAGAA Exon 30 This study Large deletion Exons 23-29 21, This study Exon 15 22 ABCC1, ABCC6 41, this study Mutation types The mutation types found in this study are summarized in Table 1. Login to comment
39 We observed two distinct nonsense mutations, R1141X and Q749X in 24 out of 117 alleles (20.5%). Login to comment
40 R1141X occurred in 22/117 alleles (18.8%) and was found in a homozygous, heterozygous, or compound heterozygous form in 19 patients (32.2%). Login to comment
52 The latter deletion was found on 13 alleles (11.1%) of 11 patients (18.6%) and was the second most frequent mutation in this study after R1141X. Login to comment
69 The R1141X mutation, the most common PXE mutation found in our cohort, is located in this domain. Login to comment
76 Molecular analysis revealed that she was homozygous for the ABCC6/MRP6 R1141X mutation. Login to comment
95 The family consisted of an affected mother, a healthy father, three severely affected, two mildly affected, Table 3 Clinical characteristics of patients from the pedigrees described in Figure 2 Genotype Pedigree Family member Age Age of onset Skin Biopsy Eyes Cardiovascular Allele 1 Allele 2 26101 II-1 44 12 + d AS ht,TIA R1141X R1141X I-1 69 n d n MI R1141X WT I-2 69 n d n Chest pain R1141X WT 26098 II-1 46 22 + d AS,MD GI hemorrhage delABCC6 del exon 23-29 II-2 40 n d AS n delABCC6 del exon 23-29 I-1 71 n 7 Drusen Multiple CI delABCC6 WT I-2 73 d d d MI del exon 23-29 WT 26095 I-3 83 52 + + AS,MD ht d II-1 66 n d n n WT WT II-2 63 48 + d MD n R1459C WT II-3 61 61 7 7 AS n R1459C WT II-4 59 n n AS,PdO n R1459C WT II-5 57 55 + d AS,neo,PdO n R1459C WT II-6 56 n d n n WT WT II-7 54 49 + d AS,neo n R1459C WT II-8 52 n d n n WT WT AS = angioid streaks; CI = cerebral infarct; GI = gastrointestinal; ht = hypertension; MD = macula degeneration; MI = myocardial infarct; n = normal; neo = neovascularization; PdO = peau d`orange; RD = retinal detachment; TIA = transient ischaemic attack; WT = wild type; + = affected; 7 = possibly affected; d = not tested. Login to comment
99 The R1141X mutant allele leads to loss of a BsiYI restriction site; the mutated allele is therefore not cut and presents with a 500 bp band. Login to comment
128 Further alignment showed that the R765Q mutation in ABCC6/MRP6 is the positional equivalent of both the R560T mutation in ABCC7,28 and the R842G mutation in ABCC8.29 Similarly, additional possible positional equivalent clusters of conserved and mutated residues were found between ABCC6/ MRP6 and ABCC2 (R1114H and R1150H),30 ABCC6/MRP6 and ABCC7 (3775 del T and W1204X),31 ABCC6/MRP6 and ABCR (R1459C and H2128R, 4220InsAGAA and R2077W, R1141X and L1631P).32,33 Interestingly, for both ABCC7 and ABCR, models were postulated in which the severity of the disease shows an inverse correlation with the predicted transport activity of the ABC protein. Login to comment
165 The ABCC6/MRP6-specific RT-PCR primers used to analyse the mutations indicated were as follows: (R1141X): ABCC6/MRP6F, 50 -CTGTCTCCAAGCCATTGGGC- 30 (cDNA position 3008-3027) and ABCC6/MRP6R, 50 - AGCCACCAGTCGCGGGAAAC-30 (cDNA position 3524- 3505); (deletion exon 23-29): ABCC6/MRP6F3, 50 - ATACGGCAGGGTGAAGGCCA-30 (cDNA position 2801- 2820) and ABCC6/MRP6R3, 50 -CAGTGCACTGTGCAAAC CAGC-30 (cDNA position 4380-4360); (R1459C): ABCC6/ MRP6F4, 50 -CTGGCTCTCTGCGGATGAAC-30 (cDNA position 4081-4100); ABCC6/MRP6R4,50 -AGAACCCGGGCA CAGTCCAT-30 (cDNA position 4432-4413). Login to comment

PMID: 12714611 [PubMed] Hu X et al: "Analysis of the frequent R1141X mutation in the ABCC6 gene in pseudoxanthoma elasticum."

No. Sentence Comment

0 Analysis of the Frequent R1141X Mutation in the ABCC6 Gene in Pseudoxanthoma Elasticum Xiaofeng Hu,1 Ron Peek,1 Astrid Plomp,1,2 Jacoline ten Brink,1 George Scheffer,3 Simone van Soest,1 Anita Leys,4 Paulus T. V. M. de Jong,1,5,6 and Arthur A. B. Bergen1,2 PURPOSE. Login to comment
1 To characterize the ABCC6 R1141X nonsense mutation, which is implicated in more than 25% of a cohort of patients from The Netherlands with pseudoxanthoma elasticum (PXE). Login to comment
4 Haplotypes of 16 patients with the R1141X mutation were determined with eight polymorphic markers spanning the ABCC6 locus. Login to comment
5 The effect of the R1141X mutation on the expression of ABCC6 was studied in leukocytes and cultured dermal fibroblasts from affected skin in patients heterozygous or homozygous for the R1141X mutation. Login to comment
8 The ABCC6 R1141X mutation was found on 19 alleles in 16 patients with PXE and occurred in heterozygous, homozygous, or compound heterozygous form. Login to comment
9 All R1141X alleles were associated with a common haplotype, covering at least three intragenic ABCC6 markers. Login to comment
11 Furthermore, the results showed that the expression of the normal allele in R1141X heterozygotes was predominant, whereas no detectable, or very low, ABCC6 mRNA levels were found in R1141X homozygotes. Login to comment
12 Immunocytochemical staining of cultured dermal fibroblasts with ABCC6-specific monoclonal antibodies showed no evidence of the presence of a truncated protein in patients with PXE who were homozygous for R1141X. Login to comment
14 A specific founder effect for the R1141X mutation exists in Dutch patients with PXE. Login to comment
15 The R1141X mutation induces instability of the aberrant mRNA. Login to comment
42 In this study, the recurrence of the R1141X mutation in 16 patients with PXE and the level of expression of ABCC6 mRNA with the R1141X mutation in (PXE) leukocytes and (PXE) fibroblasts were analyzed. Login to comment
43 In addition, the ABCC6 protein in cultured dermal fibroblasts from a patient homozygous for R1141X was studied with ABCC6-specific monoclonal antibodies. Login to comment
46 Sixteen Dutch families and patients with the R1141X mutation were included in the study. Login to comment
65 Restriction Analysis of the R1141X Mutation and Polymorphisms After identification of the R1141X mutation and detection of other intragenic polymorphisms, optimized protocols were designed by using PCR and restriction analyses. Login to comment
66 The R1141X mutation leads to the loss of a BsiYI restriction site, which was confirmed by a restriction fragment length polymorphism assay. Login to comment
74 We constructed (phase-known) haplotypes of all informative alleles from patients with the R1141X mutation. Login to comment
83 The presence or absence of the R1141X mutation in individual clones was checked with digestion with BsiYI, and, accordingly, the inserts of individual clones were assigned to be expression products from the mutant or wild-type allele. Login to comment
87 The monoclonal antibod- ies for immunocytochemical staining were M6II-7, MRPr1, and M5I-1 reactive to ABCC6, ABCC1, and ABCC5, respectively.11,12,17 RESULTS R1141X Mutation Analysis Mutation analysis of the ABCC6 gene resulted in the identification of the R1141X mutation, which accounted for up to 30% of all mutations detected in the ABCC6 gene in our cohort of patients with PXE. Login to comment
88 The R1141X mutation was caused by a C3T substitution at nucleotide 3421 in the putative eighth intracellular loop. Login to comment
90 Previously, we found that the R1141X mutation was associated with a strong increase in the prevalence of coronary artery disease.18 In our PXE cohort, R1141X was found in 19 of 29 nonde- letion alleles in DNA of 16 patients with PXE. Login to comment
92 In three patients, the R1141X mutation was observed in a homozygous form; in seven, it was in heterozygous form; and in six, it occurred in combination with other mutations in the second allele in compound heterozygous form. Login to comment
96 In the three other compound heterozygotes, the combination R1141X with a del22 bp in exon 16, a 3375delT, or Q749X was identified. Login to comment
99 The last patient, P26240, inherited the R1141X mutation and another nonsense mutation, Q749X. Login to comment
101 Founder Effect for the R1141X Mutation To determine whether the R1141X mutation originates from recurrent de novo mutational events or from founder effects, ABCC6-associated haplotypes of all patients carrying the R1141X mutation and of control subjects were constructed. Login to comment
112 The minimum common haplotype shared by all 19 alleles with the R1141X mutation was represented by the haplotype G(3803G3A)-G(2490C3G)-A(1896C3A) (Table 2). Login to comment
117 Genotype and Clinical Features of 16 Patients with the R1141X Mutation Pedigree Allele 1 Allele 2 Skin Eyes Cardiovascular 25494 R1141X Delex23-29 ϩ AS, MD HT 26026 R1141X Delex23-29 ϩ, bϩ D D 26241 R1141X Delex23-29 ϩ, bϩ PdO, AS N 26007 R1141X 1944del22 ϩ RPE changes N 26240 R1141X Q749X ϩ, bϩ AS MVP 26273 R1141X 3775delT D AS, neo D 26091 R1141X R1141X ϩ, bϩ AS GI hemorrhage 26101 R1141X R1141X ϩ AS TVI 26107 R1141X R1141X D Neo D 26093 R1141X WT ϩ AS N 26123 R1141X WT ϩ, bϩ PdO, comet N 24694 R1141X WT ϩ AS, MD CI 25908 R1141X WT ϩ AS D 26109 R1141X WT ϩ AS, neo D 26215 R1141X WT ϩ ϩ D 26242 R1141X WT ϩ, bϩ PdO MVP WT, wild type; ϩ, affected; bϩ, biopsy specimen obtained and histologic PXE changes determined after von Kossa staining; D, declined and/or no data available; AS, angioid streaks, MD, macula degeneration, PdO, peau d`orange, RPE involvement; neo, neovascularisation; comet, presence of comets; HT, hypertension; N, normal, MVP, mitral valve prolaps; GI, gastrointestinal; TVI, tricuspid valve insufficiency; CI, cerebral infarct. Login to comment
118 Effect of R1141X on ABCC6 Expression in Dermal Fibroblasts The ABCC6 mRNA with the R1141X mutation encodes a C-terminally truncated ABCC6 protein that lacks part of one of the transmembrane domains and one of the ATP-binding cassette domains. Login to comment
119 To determine the effect of this mutation on the expression of the ABCC6 gene, we analyzed dermal fibroblasts from individuals homozygous or heterozygous for R1141X and healthy control subjects. Login to comment
120 The presence of the mutations was confirmed by PCR amplification of exon 24 containing the R1141X mutation followed by restriction fragment length polymorphism analysis (Fig. 2) and direct sequencing (not shown). Login to comment
121 Next, we analyzed the amount of mRNA from alleles with the R1141X mutation. Login to comment
122 RT-PCR analyses of cultured PXE fibroblasts with the R1141X in homozygous form did not contain detectable ABCC6 mRNA. Login to comment
123 Fibroblasts from those heterozygous for the R1141X mutation appeared to have a reduced level of ABCC6 mRNA compared with the healthy control subjects (Fig. 3). Login to comment
124 The latter result indicates that the R1141X mutation affects the abundance of the mutant mRNA. Login to comment
125 To examine this in more detail, we determined the ratio of steady state transcript levels between wild-type and mutated mRNA in mononuclear blood cells and fibroblasts of patients heterozygous for the R1141X mutation. Login to comment
127 In fibroblasts of patients heterozygous for the R1141X mutation, no mRNA containing the mutation was found, whereas in blood cells, only 5% of the ABCC6 mRNA was from the mutated allele (Table 3). Login to comment
129 In parallel experiments, we determined the expression of the R1141X truncated protein in cells of patients with PXE. Login to comment
130 Cultured dermal fibroblasts of a patient with PXE homozygous for the R1141X mutation and that of a healthy control subject were analyzed by immunocytochemistry. Login to comment
134 Haplotype of the R1141X Mutation Alleles Pedigree Marker D16S 3060 972AA AG1 962 CA2 3803 G3A *3421* C3T 2490 C3G 1896 C3A CA (18) D16S 764 25908 7 3 4 G T G A 1 3 26273 5 3 4 G T G A 1 3 25494 2 3 4 G T G A 1 3 26240 3 2 4 G T G A 1 3 24694 1 2 4 G T G A 1 3 26109 2 4 G T G A 1 3 26241 4 2 4 G T G A 1 3 26101 2 3 4 G T G A 1 2 26101 5 3 4 G T G A 5 1 26026 4 3 4 G T G A 1 1 26091 4 3 4 G T G A 1 1 26091 4 12 4 G T G A 1 2 26093 2 2 4 G T G A 1 1 26007 4 12 4 G T G A 1 2 26107 2 13 4 G T G A 3 2 26107 2 13 4 G T G A 3 3 26123 2 2 4 G T G A 5 4 26215 1 2 3 G T G A 4 3 26242 2 3 2 G T G A 4 2 Distinct alleles are indicated by number. Login to comment
135 Identical haplotypes for the R1141X mutation are shaded. Login to comment
137 Underline shows homozygosity for the R1141X mutation in the proband(s). Login to comment
148 The presence of the R1141X mutation was confirmed by digestion with BsiYI of PCR products containing exon 24. Login to comment
151 The R1141X mutant allele leads to the loss of the BsiYI restriction site and produces a single fragment of 100 bp. Login to comment
153 These results suggest that the R1141X mutation in ABCC6 does not lead to detectable amounts of truncated protein. Login to comment
154 Phenotypes of Patients with the R1141X Mutation A summary of clinical data available from the 16 patients with PXE with R1141X mutations is shown in Table 1. Login to comment
159 In summary, in all patients homozygous or compound heterozygous for the R1141X mutation, we observed ocular and skin abnormalities and, less frequently, cardiovascular problems. Login to comment
160 However, because the expression of the disease in these tissues is highly variable among our patients, we could not correlate a distinct phenotype with the R1141X mutation. Login to comment
161 DISCUSSION R1141X Mutation Analysis We detected the R1141X mutation in homozygous, heterozygous, and compound heterozygous forms. Login to comment
162 In nine patients the R1141X mutation was present in a homozygous form or a compound heterozygous form. Login to comment
164 In seven patients, we detected R1141X in heterozygous form. Login to comment
166 However, despite extensive screening, we have not yet found another mutation or deletion in the second, non-R1141X, ABCC6 allele. Login to comment
168 Consequently, the pathologic molecular aspect of the R1141X mutation is most likely compatible with the frequently occurring autosomal recessive inheritance in PXE. Login to comment
169 Nonetheless, potential mild expression of the disease in carriers of the R1141X mutation warrants further investigation. Login to comment
170 Founder Effect for the R1141X Mutation Mutation analysis of the ABCC6 gene in patients with PXE has yielded 57 different ABCC6 mutations to date.15 The R1141X mutation was reported to be the most common mutation by us and others, especially in European patients.14,15 Recently, we also found that R1141X may be associated with a strong increase in the prevalence of coronary artery disease.18 The association between its high frequency and the geographical distribution could reflect a founder effect from a common ancestor. Login to comment
171 To test this hypothesis, we analyzed the R1141X mutation in more detail in this study. Login to comment
172 The majority of our R1141X mutant alleles (17/19) shared a common haplotype spanning at least one ABCC6 flanking marker. Login to comment
179 Top: RT-PCR analysis of ABCC6 expression in cultured dermal fibroblasts from patients heterozygous or homozygous for the R1141X mutation. Login to comment
183 Staining with MRP1 and MRP6 monoclonal antibodies of a monolayer of dermal fibroblasts from a healthy individual and a patient with PXE heterozygous for the R1141X mutation. Login to comment
185 The Expression Ratio of ABCC6 Wild-Type and Mutated mRNA Genotype Tissue WT Allele (%) Mutant Allele (%) WT/WT Blood 20/20 (100) No R1141X/WT Blood 38/40 (95) 2/40 (5) R1459C/WT Blood 52/100 (52) 48/100 (48) The number of PXE heterozygotes carrying an ABCC6 R1141X (R1141/X) or R1459C (R1459C/WT) mutation and a healthy control subject with wild-type ABCC6 (WT/WT). Login to comment
187 Predominant Expression of the Normal ABCC6 Allele in Patients with PXE Heterozygous for the R1141X Mutation For several mammalian mRNAs, it has been shown that a nonsense mutation or a frameshift mutation that generates a nonsense codon may greatly influence the abundance of these transcripts. Login to comment
188 A specific mechanism called nonsense-mediated mRNA decay (NMD) accelerates decay of transcripts coding for truncated proteins and thus minimizes potential metabolic damage.19,20 We found no detectable ABCC6 mRNA in patients with PXE who were homozygous for the R1141X mutation. Login to comment
189 Consistent with this observation, no ABCC6 protein was detected in cultured dermal fibroblasts of a patient homozygous for R1141X. Login to comment
190 Using a more quantitative approach, we found that in cultured dermal fibroblasts of a R1141X heterozygote, only transcripts from the wild-type allele were detected. Login to comment
191 In mononuclear blood cells of a R1141X heterozygote the mutated transcript was detected, but the abundance was reduced to 5% of total ABCC6 mRNA. Login to comment
192 Our results suggest that the R1141X mutation induces instability of the aberrant ABCC6 mRNA, which leads to a reduced abundance of the corresponding transcript due to alterations in RNA processing by NMD. Login to comment
197 Features of the Phenotype The clinical variability in PXE was demonstrated previously2,24 and also occurred in our R1141X patient cohort. Login to comment
203 CONCLUSION In summary, this study presents evidence that the frequent occurrence of the ABCC6 R1141X mutation in Dutch patients with PXE was due to a founder effect. Login to comment
204 The PXE phenotype of the R1141X mutation is most likely due to a complete loss of function or functional haploinsufficiency of the ABCC6 gene. Login to comment
205 No clear correlation between the R1141X genotype and phenotype could be established in the cohort studied. Login to comment

PMID: 12850230 [PubMed] Hu X et al: "Pseudoxanthoma elasticum: a clinical, histopathological, and molecular update."

No. Sentence Comment

179 The R1141X mutation in exon 24 was reported by four research groups and appears to be a common mutation underlying PXE. Login to comment
180 R1141X generates a stop codon at cDNA position 3421 and presumably results in a reduction in mutant mRNA levels by nonsense-mediated RNA decay.25,69 Mutations appear to be also frequent in exons 28-30, corresponding to the NBF2 region, where the function of the protein might be abolished by the change in a single amino acid. Login to comment
193 TABLE 3 Summary of ABCC6 Mutations in PXE Patients Mutation Protein Alteration Nucleotide Substitution Location Reference Nonsense Q378X 1132C Ͼ T Exon 9 16,107 R518X 1552C Ͼ T Exon 12 88 Y768X 2304C Ͼ A Exon 18 67 R1030X 3088C Ͼ T Exon 23 67 R1141X 3421C Ͼ T Exon 24 12,45,67,107,111,112,133 R1164X 3490C Ͼ T Exon 24 88,112 Q1237X 3709C Ͼ T Exon 26 67 R1398X 4192C Ͼ T Exon 29 67 Missense T364R 1091C Ͼ G Exon 9 107 N411K 1233T Ͼ G Exon 10 67 A455P 1363G Ͼ C Exon 11 142 R518Q 1553G Ͼ A Exon 12 67,142 F568S 1703T Ͼ C Exon 13 67 L673P 2018T Ͼ C Exon 16 67 R765Q 2294G Ͼ A Exon 18 67 R1114P 3341G Ͼ C Exon 24 67 S1121W 3362C Ͼ G Exon 24 67 R1138W 3412C Ͼ T Exon 24 111 R1138Q 3413G Ͼ A Exon 24 67,111 R1138P 3413G Ͼ C Exon 24 67 G1203D 3608G Ͼ A Exon 25 67 V1298F 3892G Ͼ T Exon 28 67 T13011 3902C Ͼ T Exon 28 67 G1302R 3904G Ͼ A Exon 28 67 A1303P 3907G Ͼ C Exon 28 67 R1314W 3940C Ͼ T Exon 28 67 R1314Q 3941G Ͼ A Exon 28 67 G1321S 3961G Ͼ A Exon 28 67 R1339C 4015C Ͼ T Exon 28 67,133 Q1347H 4041G Ͼ C Exon 28 67 G1354R 4060G Ͼ C Exon 29 107,142 D1361N 4081G Ͼ A Exon 29 67 11424T 4271T Ͼ C Exon 30 67 Frameshift Splicing IVS21 ϩ 1G ϾT Intron 21 67,142 IVS26-1G ϾA Intron 26 67,111,112 Deletion 179del9 Exon 2 107 179-195del Exon 2 67 960delC Exon 8 88 1944del22 Exon 16 12 1995delG Exon 16 67 2322delC Exon 18 67 2542delG Exon 19 67 3775delT Exon 27 12,67 4101delC Exon 29 67 Insertion 938-939insT Exon 8 67 4220insAGAA Exon 30 12 Intragenic deletion Exon 23-29 67,112 Exon 15 67 Intergenic deletion ABCC6 12,88 LOCAL RETINAL TRANSPORT FUNCTION OF ABCC6 ABCC6 Expression in the Retina Bergen et al detected ABCC6 expression in various tissues in man.12 Low expression levels of ABCC6 were observed in the retina as well as other tissues usually affected by PXE, including skin and vessel wall. Login to comment

PMID: 12901863 [PubMed] Sinko E et al: "Subcellular localization and N-glycosylation of human ABCC6, expressed in MDCKII cells."

No. Sentence Comment

11 Furthermore, it was recently found that the presence of the most common mutation (R1141X) in the ABCC6 gene is associated with an increased risk of premature coronary artery disease [10]. Login to comment

PMID: 12928920 [PubMed] Morcher M et al: "Heterozygous carriers of Pseudoxanthoma elasticum were not found among patients with cervical artery dissections."

No. Sentence Comment

45 However, the R1141X muTable ABCC6sequencevariationin12patientswithsCADand2patientswithPXE exon nucleotide Amino-acid Occurrence Occurrence position change among patients among controls 10 1233T¡C synonymous sCAD not tested 10 1245G¡A synonymous sCAD not tested 15 1890C¡G synonymous sCAD not tested 15 1896C¡A H623Q sCAD + 19 2490C¡T synonymous sCAD not tested 20 2631C¡A synonymous sCAD not tested 22 2835C¡T synonymous sCAD not tested 22 2836C¡A L946I PXE - 23 3190C¡T R1064W sCAD + 24 3389C¡T T1130M PXE - 27 3803G¡A R1268Q sCAD + tation is common in European patients, whereas a large deletion of exons 23-26 is repeatedly found in patients from the United States [22]. Login to comment

PMID: 14631379 [PubMed] Gotting C et al: "Assessment of a rapid-cycle PCR assay for the identification of the recurrent c.3421C>T mutation in the ABCC6 gene in pseudoxanthoma elasticum patients."

No. Sentence Comment

23 The first mutations in the ABCC6 gene were identified in the genomic DNA isolated from PXE patients, and comparative family analysis could confirm most of these mutations to be associated with the PXE phenotype.7-9,14-18 A frequent mutation detected in the ABCC6 gene in PXE patients is the nonsense mutation c.3421C4T (p.R1141X), resulting in a truncated protein that lacks the second ATP-binding domain of the native MRP6.7-9,19,20 Another mutation, which is frequently found in American PXE patients, is a large deletion including exons 23-29,17 which also leads to a loss of the second ATP-binding site of MRP6. Login to comment
122 (a) Schematic structure of the MRP6 protein and localization of the mutations c.3421C4T (p.R1141X), c.3389C4T (p.T1130 M) and c.3341G4A (p.R1114 H). Login to comment

PMID: 14667841 [PubMed] Boraldi F et al: "Multidrug resistance protein-6 (MRP6) in human dermal fibroblasts. Comparison between cells from normal subjects and from Pseudoxanthoma elasticum patients."

No. Sentence Comment

3 In vitro dermal fibroblasts from normal and PXE subjects, homozygous for the R1141X mutation, were compared for their ability to accumulate and to release fluorescent calcein, in the absence and in the presence of inhibitors and competitors of the MDR-multidrug resistance protein (MRP) systems, such as 3-(3-(2-(7-choro-2 quinolinyl) ethenyl)phenyl ((3-dimethyl amino-3-oxo-propyl)thio) methyl) propanoic acid (MK571), verapamil (VPL), vinblastine (VBL), chlorambucil (CHB), benzbromarone (BNZ) and indomethacin (IDM). Login to comment
33 We compared the efficiency of the MDRyMRP system of normal fibroblasts with that of fibroblasts from PXE patients homozygous for the nucleotide change 3421 C™T in exon 24 of the ABCC6 gene resulting in the creation of a premature stop codon at R1141X (Le Saux et al., 2000, 2001). Login to comment
92 Only fibroblasts from patients homozygous for the R1141X mutation were used in the present study. Login to comment
112 Therefore, MRP6 deficiency, due to the R1141X mutation, induces fibroblasts to accumulate calcein in higher amount and to release it in a time 25% longer than normal cells. Login to comment
149 Patients were homozygous for the mutation R1141X (see further for details) showing no detectable mRNA for MRP6 (Le Saux et al., 2000). Login to comment
160 R1141X mutation identification Genomic DNA was isolated from blood leukocytes of PXE patients and purified with a QIAamp blood kit (Qiagen), according to standard procedures. Login to comment

PMID: 14764080 [PubMed] Annovazzi L et al: "High levels of desmosines in urine and plasma of patients with pseudoxanthoma elasticum."

No. Sentence Comment

62 Four patients were homozygous for the R1141X mutation on both alleles, two patients were homozygous for a mutation on exons 9 and 30, respectively.All the others were compound heterozygous with mutations on exons 9, 10, 12, 23, 24 and 28. Login to comment

PMID: 15086542 [PubMed] Chassaing N et al: "Novel ABCC6 mutations in pseudoxanthoma elasticum."

No. Sentence Comment

3 We found that arginine codon 518 was, with the previously described R1141X and EX23_29del, a recurrently mutated amino acid (11.5% of the mutations detected for each variant R518Q and R518X). Login to comment
28 Phenotype and genotype of the patients studied Patient Origin Sex Age (y) Amino acid variation Nucleotide variation Exon Phenotype C O CV 1 France/Greece F 26 R1141X 3421C4T 24 1 0 0 E1400K 4198G4A 29 2 France F 31 V74del 220-222del 3 1 1 0 V74del 220-222del 3 3-1 Morocco F 20 E1400K 4198G4A 29 1 0 0 E1400K 4198G4A 29 3-2 M 18 E1400K 4198G4A 29 1 0 2 E1400K 4198G4A 29 4 France F 36 A999_S1403del EX23_29del 23-29 1 1 0 Splicing alteration IVS25-3C4A 5 France F 44 ?/? Login to comment
29 2 0 0 6 France M 15 R1141X 3421C4T 24 2 0 1 R1141X 3421C4T 24 7 Morocco F 26 R518Q 1553G4A 12 1 1 1 R518Q 1553G4A 12 8 Turkey F 21 A766D 2297C4A 18 1 0 0 A766D 2297C4A 18 9 France F 41 R518Q 1553G4A 12 1 0 0 T1130M 3389C4T 24 10 France F 30 R518X 1552C4T 12 1 0 0 R518X 1552C4T 12 11-1 Algeria F 75 NA 1 0 0 T1130M 3389C4T 24 11-2 M 39 D1238H 3712G4C 26 1 0 0 11-3 F 36 Q363_R373del 1088-1120del 9 2 0 0 D1238H 3712G4C 26 12 France M 58 ?/? Login to comment
33 1552C4T 12 1 0 0 18 France F 31 R1141X 3421C4T 24 1 0 0 W1223X 3668G4A 26 19-1 France M 18 R1164X/? Login to comment
46 The two known recurrent mutations (R1141X and EX23_29del) account respectively for 13% and 7% of the mutations detected in the French families included in our study, and were absent from the families originating from Algeria, Morocco, and Turkey. Login to comment
58 The results are summarized in Table II. The recurrent mutated allele R1141X shares a common haplotype identical-by-descent in the French families (families 1, 6, and 18), which is consistent with the same geographic origin of these patients. Login to comment
59 R1141X is the most frequent mutation found in the European population, and haplotype analysis of additional European patients would be helpful to establish whether this mutant allele is inherited from a common ancestor. Login to comment
90 In two families, the recurrent recessive mutation R1141X was identified in affected patients (Bergen et al, 2000). Login to comment

PMID: 15098239 [PubMed] Plomp AS et al: "Does autosomal dominant pseudoxanthoma elasticum exist?"

No. Sentence Comment

130 Mother35Peaud`orangeIncreasedechogenicityofkidneys andpancreas AppelmansandLebas[1953]a Femaleproband50AS,bleeding,MDCharacteristicofPXEHypertension Son28AS,yellowishretinallesionsManypapuleshighonback Daughter25AS,yellowishretinallesionsNormal Extensive screening of the ABCC6 gene revealed a R1141X mutation in only one allele. Login to comment
133 However, he did have the R1141X mutation. Login to comment
138 She also had the R1141X mutation in a single allele. An aunt (II-3) had some yellowish papules on the neck and the cubital fossae. Login to comment
141 She also was heterozygous for the R1141X mutation. Login to comment
144 One of the uncles had the R1141X mutation. Login to comment
203 ABCC6 mutation analysis of a control population of 1,057 persons in our lab yielded 8 carriers of the R1141X mutation [Trip et al., 2002]. Login to comment
223 The R1141X mutation was found in one allele of these three individuals and in a healthy uncle Fig. 2. Pedigree of family 1. Login to comment
234 Expression studies in our lab suggested that the R1141X mutation leads to absence of protein by nonsense-mediated RNA decay [Hu et al., 2003c]. Login to comment
236 The patients with definite PXE, in whom one R1141X mutation was found, could have a second, as yet unknown, mutation. Login to comment
260 Recently, heterozygosity for the R1141X mutation was found to be associated with increased risk of cardiovascular disease [Trip et al., 2002]. Login to comment

PMID: 15459974 [PubMed] Gheduzzi D et al: "ABCC6 mutations in Italian families affected by pseudoxanthoma elasticum (PXE)."

No. Sentence Comment

64 PXE-causative Mutations Recognized (on one and both alleles) in Italian Patients Family/ Proband Affected subjects Age / gender Clinical score Tot Mutations* Allele 1 Allele 2 Mutation type 001 32 F S2,E2 4 p.R518Q p.T1130MI-3097 002 36 M S3,E2,V2,C2 9 p.R518Q p.T1130M I-3013 001 46 F S1,E3 4 p.R1339C None found I-3094 001 57 F S2,E2 4 p.C440G p.P1346S I-3103 001 57 M E2 2 p.V810M p.R1114C I-3076 001 57 F S2,E4,V3 9 p.R1339C p.R1339C I-3016 001 69 F S3,E2,V2 7 p.N411K p.R1138Q missense I-3082 001 23 M S1,E2 3 p.R518Q p.R1141X I-3074 001 27 F S2,E2 4 p.T364R p.R518X I-3015 001 27 F S2,E3 5 p.Q378X p.R600G I-3062 001 45 M S2,E4,V2 8 p.R1141X p.E1400K 001 50 F S1 1 p.R1275X p.E1400K 002 60 F S3,E3 6 p.R1275X p.E1400K I-3067 003 66 F S2,E2 4 p.R1275X p.E1400K 001 61 F S3,E2 4 p.R518Q p.R1141XI-3027 002 63 F S3,E4,V3 10 p.R518Q p.R1141X missense + nonsense 001 23 F S3,E2 5 p.R1141X p.R1141XI-3056** 002 32 M S2,E2 4 p.R1141X p.R1141X 001 27 F S1,E2 3 p.R1141X p.R1141XI-3057** 002 31 M S3,E2 5 p.R1141X p.R1141X 001 28 M S1,E2 3 p.R1141X None foundI-3045 002 32 F S3,E2,V1 6 p.R1141X None found I-3107 001 29 M S2,E1 3 p.R1030X p.R1141X I-3073 001 31 F S3,E2 5 p.R1141X p.R1141X I-3111 001 32 F S1,E2 3 p.R1141X p.R1141X I-3090 001 34 F S2,E1 3 p.R1141X p.R1141X I-3001 001 37 F S3,E2,V2 7 p.R1030X None found 001 40 F S2,E2 4 p.R1141X p.R1141XI-3007** 002 48 F S1,E2 3 p.R1141X p.R1141X I-3114 001 40 M S2,E2,V3,C1,G2 10 p.R518X p.R518X I-3054 001 44 F S2,E3 5 p.R518X p.R518X 001 47 F S3,E4,C2,G1 10 p.R1141X p.R1141XI-3055** 002 50 F S3,E3 6 p.R1141X p.R1141X 001 50 F S3,E4,V3,C2 12 p.R518X p.R1030X 002 52 F S3,E4,V3 10 p.R518X p.R1030X I-3017 003 55 F S3,E2 5 p.R518X p.R1030X I-3100 001 52 M S3,E3 6 p.Q378X p.Q378X I-3051 001 53 F S3,E4,V2 9 p.R1141X p.R1141X I-3034 001 53 M S3,E4,V3 10 p.R1141X p.R1141X I-3093 001 57 F S3,E3,V2,C3 11 p.R518X None found I-3087 001 57 F S3,E4,V2,C2 11 p.Q378X p.Q378X I-3040 001 60 F S3,E4,V2 9 p.R1141X None found I-3033 001 62 F S3,E4 7 p.R1141X p.R1141X nonsense I-3026 001 36 F S3,E2,G1 6 p.R518X c.2248-2_2248- 1del I-3024 001 40 F S1,E2,V3 6 p.R518X p.L1182PfsX96 I-3072 001 41 F S2,E2,C2 6 p.M1127T c.3736-1G>A I-3002 001 50 F S3,E2 5 p.A820P c.3736-1G>A others Family/ Proband Affected subjects Age / gender Clinical score Tot Mutations* Allele 1 Allele 2 Mutation type 002 57 F S2,E4 6 p.A820P c.3736-1G>A I-3008 001 53 F S2,E2,C1 5 p.M1440CfsX24 p.M1440CfsX24 Patients are identified by an international code: I = Italian, 3001 = family number (European patients are numerated from 3000), 001 = subject number. Login to comment
72 ABCC6/MRP6 Mutations Found in Italian PXE Patients Number of families INTRON EXON cDNA* PROTEIN* References 1 9 c.1091C>G p.T364R Pulkkinen et al., 2001 3 9 c.1132C>T p.Q378X Pulkkinen et al., 2001; Cai et al., 2001 1 10 c.1318T>G p.C440G Present study 1 10 c.1233T>G p.N411K Le Saux et al., 2001 7 12 c.1552C>T p.R518X Meloni et al., 2001; Chassaing et al., 2004 3 12 c.1553G>A p.R518Q Le Saux et al., 2001; Chassaing et al., 2004 1 14 c.1798C>T p.R600G Present study 1 17 c.2248-2_2248- 1del - Present study 1 19 c.2428G>A p.V810M Present study 1 19 c.2458G>C p.A820P Present study 3 23 c.3088C>T p.R1030X Le Saux et al., 2001 1 24 c.3340C>T p.R1114C Present study 1 24 c.3380C>T p.M1127T Present study 1 24 c.3389C>T p.T1130M Chassaing et al., 2004; Gotting et al., 2004 1 24 c.3413G>A p.R1138Q Le Saux et al., 2000; Ringpfeil et al., 2000; Le Saux et al., 2001 13 24 c.3421C>T p.R1141X Bergen et al., 2000; Germain et al., 2000; Ringpfeil et al., 2000; Le Saux et al., 2001; Pulkkinen et al., 2001; Uitto et al., 2001; Hu et al., 2003 ; Gotting et al., 2004 1 25 c.3544_3544dupC p.L1182PfsX96 Present study 2 26 c.3736-1G>A - Ringpfeil et al., 2000; Le Saux et al., 2001 1 27 c.3823C>T p.R1275X Present study 2 28 c.4015C>T p.R1339C Le Saux et al., 2001 1 28 c.4036C>T p.P1346S Present study 2 29 c.4198G>A p.E1400K Chassaing et al., 2004 1 30 c.4318_4318delA p.M1440CfsX24 Present study The number of families in which a specific mutation was found (in heterozygous and in homozygous state) is reported. Login to comment
75 In the PXE patients examined, exon 24 of the ABCC6 gene was the most affected one, and c.3421C>T (p.R1141X) was the most frequent mutation, being homozygous in 7 of 38 families (18.4%), and heterozygous in another 6 unrelated families (15.8%), including the 2 families (3 patients) in whom it was the only detected mutation. Login to comment
76 Therefore, the p.R1141X mutation was present in 26.3% of all the alleles examined (20/76). Login to comment
81 In order to identify a possible founder origin of recurrent disease-associated alleles, a limited haplotype analysis was performed in 11 unrelated families carrying the same mutation (p.Q378X, p.R518X, p.R1141X) in homozygous state (data not shown). Login to comment
84 The analysis of the seven families with the p.R1141X mutated allele showed common haplotypes, suggesting the presence of a common ancestor. Login to comment
85 Comparison of the analysis of 9 intragenic single-nucleotide polymorphisms, evaluated in Italian as well as in French patients (Chassaing et al., 2004), showed identical alleles, suggestive for a founder origin of p.R1141X mutation in European PXE patients. Login to comment
111 In particular, by considering patients homozygous for the most recurrent p.R1141X mutation, that is associated with the almost complete absence of MRP6 (Le Saux et al., 2001; Hu et al., 2003), the correlation between total clinical score and age was highly consistent (p<0.01). Login to comment
118 Some were recurrent mutations (p.Q378X, p.R518X, p.R518Q, p.R1141X), however the majority of mutations were sporadic variants. Login to comment
119 The most frequent p.R1141X PXE-related allele shared a common haplotype identical-by-descent in seven Italian families homozygous for this mutation. Login to comment
128 As a further example, patient I- 3055-001, who was also a strong smoker, was the only PXE patient homozygous for the p.R1141X mutation with heart and gastro-intestinal alterations, whereas her sister had only eye and skin lesions, underlining the importance of exogenous factors that may interfere with elastin deposition and degradation. Login to comment

PMID: 15645653 [PubMed] Noji Y et al: "Identification of two novel missense mutations (p.R1221C and p.R1357W) in the ABCC6 (MRP6) gene in a Japanese patient with pseudoxanthoma elasticum (PXE)."

No. Sentence Comment

16 Le Saux et al demonstrated that the nonsense mutation p.R1141X and a large deletion spanning from exon 23 to exon 29 were relatively common mutations in a cohort of 122 patients from the United Kingdom, the United States, South Africa, Italy, Germany, and Belgium (5). Login to comment
56 We have found neither the nonsense variant p.R1141X nor the large deletion ABCC6del23-29 in our patients. Login to comment
85 In two families, the recurrent recessive mutation p.R1141X was identified in affected patients (3). Login to comment

PMID: 15723264 [PubMed] Hendig D et al: "New ABCC6 gene mutations in German pseudoxanthoma elasticum patients."

No. Sentence Comment

35 The most frequent mutation in PXE patients of European descent is the nonsense mutation p.R1141X [15, 18, 19]. Login to comment
74 In addition, the presence of the frequent c.3421C>T (p.R1141X) mutation was analyzed in all patients and relatives as previously reported by us [18]. Login to comment
75 The nonsense mutation p.R1141X was the most frequent mutation found in the panel of PXE patients investigated in the present study. Login to comment
77 Heterozygous carriers but no homozygous carriers of the p.R1141X mutation were identified among the 54 unaffected relatives (data not shown). Login to comment
78 One heterozygous carrier of the nonsense mutation p.R1141X was detected among 910 healthy Westphalian blood donors. Login to comment
104 The nonsense mutation p.R1141X, which was identified in 34 (44.7%) PXE patients, was the most frequent mutation in our cohort of German PXE patients. Login to comment
107 In contrast to the p.R1141X mutation, most of these variations were unique in the cohort studied. Login to comment
134 All but two of the PXE patients who were identified to be heterozygous carriers of the six novel mutations (p.M751K, p.R760W, p.L851P, p.S1403R, and c.2835_ 2850del16) were also found to carry one other PXE-causing ABCC6 mutation (c.2787+1G>T, p.R1141X, c.3736-1G>A, p.R1268Q). Login to comment

PMID: 15727254 [PubMed] Hu X et al: "Efficient molecular diagnostic strategy for ABCC6 in pseudoxanthoma elasticum."

No. Sentence Comment

4 The two most frequent mutations, R1141X and an ABCC6 del exons 23-29, as well as a core set of mutations, were identified by restriction enzyme digestion and size separation on agarose gels. Login to comment
57 Six nucleotide changes, including 2,294g Ǟ a (R765Q in exon 18), 3,421c Ǟ t (R1141X in exon 24), 3904g Ǟ a (G1302R in exon 28), 3,907g Ǟ c (A1303P in exon 28), 3,775del T (W1259 frameshift in exon 27), and 4,377c Ǟ t (R1459C in exon 30) were determined by the digestion of PCR fragments with restriction enzymes Sma I, Bsi YI, Nci I, Hea III, Bst NI, and Aci I, respectively. Login to comment
95 RESULTS OF THE MUTATION ANALYSIS IN THE ABBC6 GENE IN 76 PATIENTS Sequence Type AA change variation Location Alleles Statusa Phaseb Method Nonsense Q749X 2247 C → T Exon 17 2 ht 3 DHPLC R1141X 3421 C → T Exon 24 35 hm.ht.ch 1 Bsi YI Missense R765Q 2294G → A Exon 18 1 ht 2 Sma I R1114H 3341G → A Exon 24 1 ht 3 dHPLC T1130M 3390C → T Exon 24 2 ch 3 dHPLC R1221C 3663C → T Exon 26 1 ch 3 dHPLC G1302R 3904G → A Exon 28 1 ht 2 Nci I A1303P 3907G → C Exon 28 1 ch 2 Hae III D1326N 3999G → A Exon 28 1 ht 3 dHPLC K1394N 4182G → T Exon 29 1 ch 3 dHPLC R1459C 4377C → T Exon 30 1 ht 2 Aci I Frameshift Splicing IVS17-12delTT Intron 17 1 ht 3 dHPLC IVS26-1G → A Intron 26 1 ht 3 dHPLC Deletion 1944del22 Exon 16 2 ht,ch 2 PCR 4182delG Exon 29 6 hm,ht 3 dHPLC 3775delT Exon 27 11 hm,ht 2 Bst NI 3821del48 Exon 27 1 ht 2 PCR Insertion 4220insAGAA Exon 30 1 ht 3 dHPLC Deletion A995del405 del exon 23-29 Exon 23-29 17 hm,ht,ch,hem 1 PCR ABCC6 2 ht 4 FISH ahm, homozygote; ht, heterozygote; ch, compound heterozygote; hem, hemizygote. Login to comment
98 ABCC6 mutation analysis. Phase I: Detection of the R1141X mutation in exon 24 and deletion of exons 23-29. Login to comment
100 Lane 1, the R1141X mutation disrupts the Bsi YI site in the wild-type sequence and results in a single PCR fragment of 100 bp; lane 2, the wild-type allele was cleaved into two Bsi YI fragments of 88 bp and 12 bp (latter band not visible). Login to comment
115 Phase 1: Rapid detection of the founder mutation R114X and deletion of exons 23-29 The founder mutation, R1141X (Hu et al., 2003b), was found in 35 out of 89 mutant alleles (39.3%). Login to comment
116 R1141X was the most common PXE mutation in our cohort. Login to comment
154 Phase 2: Rapid detection of a core set of mutations After screening of R1141X and del exons 23-29, a core set of seven additional mutations was rapidly identified by PCR and PCR-RFLP. Login to comment
172 The current strategy is especially efficient for the European population, in which a number of PXE mutations occur very frequent, i.e., R1141X (39.3%) and del exon 33-29 (19%). Login to comment

PMID: 15837081 [PubMed] Wegman JJ et al: "Patients with premature coronary artery disease who carry the ABCC6 R1141X mutation have no Pseudoxanthoma Elasticum phenotype."

No. Sentence Comment

0 Patients with premature coronary artery disease who carry the ABCC6 R1141X mutation have no Pseudoxanthoma Elasticum phenotype Jurgen J. Wegmana , Xiaofeng Hub , Hendra Tanc , Arthur A.B. Bergenb , Mieke D. Tripd , John J.P. Kastelein, Yvo M. Smulderse,* a Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands b The Netherlands Ophthalmic Research Institute, Amsterdam, The Netherlands c Department of Ophthalmology, Academic Medical Center, University of Amsterdam, The Netherlands d Department of Cardiology, Academic Medical Center, University of Amsterdam, The Netherlands e Department of Internal Medicine, VU University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands Received 26 February 2004; received in revised form 28 June 2004; accepted 5 July 2004 Available online 2 February 2005 Abstract Background: Pseudoxanthoma elasticum (PXE) is an inherited disorder of elastic tissue. Login to comment
1 We recently found that heterozygosity for the frequent (0.8% prevalence in Dutch population) R1141X mutation in the PXE gene coding for the ABCC6 transporter, is associated with a fourfold risk of premature coronary artery disease. Login to comment
3 The objective of our study was to determine if skin and/or eye abnormalities related to a PXE phenotype could be found in patients with premature coronary artery disease, with and without the R1141X mutation. Login to comment
4 Methods: R1141X mutation carriers with premature coronary artery disease (cases) and patients with premature coronary artery disease with no-or not known-mutation (controls) were studied. Login to comment
8 Conclusions: Carriers for the ABCC6 R1141X mutation, which is frequent and confers a high risk of premature coronary artery disease, do not commonly have skin or eye abnormalities consistent with a mild PXE phenotype. Login to comment
32 We subsequently observed a relatively high prevalence of 3.2% heterozygosity for the R1141X mutation in the ABCC6 gene, in a population with premature coronary artery disease, as opposed to 0.8% prevalence in a large population-based sample [17]. Login to comment
33 Heterozygosity for the R1141X mutation certainly does not commonly lead to the typical PXE phenotype, but how often a mild PXE phenotype characterises such patients is unknown. Login to comment
34 In the present study, we specifically looked for typical skin changes and ocular abnormalities in patients with premature coronary artery disease and heterozygosity for the R1141X mutation, in order to assess if these patients have mild PXE-like characteristics. Login to comment
36 This was done for two reasons: First, R1141X is not the only mutation causing PXE in Dutch patients [7] and, second, the phenotypical presentations, particularly the angioid streaks in fundo, are not entirely specific for PXE [11]. Login to comment
42 Seven patients who were under the age of 50 years at the time of their coronary artery disease event (occurring between 1995 and 2001), who carried the R1141X mutation in the ABCC6 gene, and who we were able to contact and obtain consent from, were selected as cases from the database of the atherosclerosis outpatient clinic [17]. Login to comment
45 In 21 patients in the control group, the absence of the R1141X mutation in the ABCC6 gene was confirmed by DNA analysis. Login to comment
64 Results The summary demographic and clinical data of the 7 R1141X mutation-positive patients and the 31 controls are listed in Table 1. Login to comment
74 Discussion Our study examined discrete PXE-like characteristics in 38 patients with premature coronary artery disease, 7 of whom were identified as carriers of the R1141X mutation in the ABCC6 gene. Login to comment
78 Second, more importantly, our results suggest that, although heterozygosity for the R1141X PXE mutation is frequent and confers a sharply increased risk of coronary artery disease [17], these patients, or at least the majority of them, cannot easily be identified by a discrete PXE phenotype. Login to comment
82 The absence of a macroscopically detectable dermatological and retinal PXE phenotype in coronary artery disease patients who are carriers of the R1141X mutation is important. Login to comment
83 The prevalence of this mutation in a large (n=1057) sample of the Dutch population was 0.8%, and the odds ratio for coronary artery disease associated with the Table 1 Summary of demographic and clinical data on ABCC6/MRP6 R1141X mutation-positive patients and controls R1141X positive Control Number of patients 7 31 Male gender 5 (71%) 24 (77%) Age (years) 42.9 (4.8) 40.6 (5.7) History of smoking 4 (57%) 24 (77%) First-degree family history of CAD 4 (57%) 7 (23%) Systolic blood pressure (mmHg) 127.1 (14.1) 129.5 (14.7) Diastolic blood pressure (mmHg) 78.6 (6.3) 79.3 (8.3) Total cholesterol (mmol/l) 5.7 (1.0) 5.4 (1.1) HDL cholesterol (mmol/l) 1.1 (0.2) 1.1 (0.3) LDL cholesterol (mmol/l) 3.8 (1.1) 3.5 (0.9) Triglycerides (mmol/l) 1.9 (0.9-3.1) 1.4 (0.4-4.6) Skin/fundus abnormalities none none Data are number (%), mean (standard deviation), or median (range). Login to comment
84 Table 2 Individual patient data on the ABCC6/MRP6 R1141X mutation-positive patients, who all had a coronary event before the age of 50 years Patient #1 Patient #2 Patient #3 Patient #4 Patient #5 Patient #6 Patient #7 Gender male male male male female female male Age at time of first coronary event 37 50 43 48 42 38 42 Family history parental parental parental none sibs none none Smoking history (pack years) 25 30 none 60 none none 12 Blood pressure (mmHg) 115/80 120/80 130/80 110/70 125/75 150/90 140/75 Total cholesterol (mmol/l) 5.4 5.2 5.2 6.7 6.7 4.1 6.6 LDL cholesterol (mmol/l) 3.1 3.4 3.2 4.4 5.1 2.3 5.0 HDL cholesterol (mmol/l) 0.9 1.0 1.3 1.0 0.9 1.2 1.2 Triglycerides (mmol/l) 3.1 1.7 1.6 2.8 1.6 1.4 0.9 Skin abnormalities absent absent absent absent absent absent absent Fundus examination normal normal normal normal normal normal normal J.J. Wegman et al. / International Journal of Cardiology 100 (2005) 389-393 391 mutation was 4.2 [17]. Login to comment
86 However, given our present findings in coronary artery disease patients, and the rarity of the PXE phenotype in the population, it appears that the majority of individuals who are heterozygous for R1141X do not have the typical PXE phenotype. Login to comment
101 Secondly, the R1141X mutation was not determined in all controls. Login to comment
102 Statistically, however, the chance of finding an appreciable number of R1141X mutations in these 10 patients is small. Login to comment
103 Even if 1 or 2 of these patients would be R1141X-positive, this would in no way affect our conclusion, but only strengthen our deduction that such patients do not commonly have a PXE phenotype. Login to comment
109 In a recent study, in which we presented the mutation spectrum of ABCC6 in 59 PXE patients from The Netherlands, we identified the R1141X to be the most common mutation [7]. Login to comment
110 The R1141X mutation was identified in 32.2 % of Dutch patients [24]. Login to comment

PMID: 15888484 [PubMed] Gorgels TG et al: "Disruption of Abcc6 in the mouse: novel insight in the pathogenesis of pseudoxanthoma elasticum."

No. Sentence Comment

31 Furthermore, we found that a frequent (founder) mutation in ABCC6, R1141X (10), may be associated with a strong increase in the prevalence of premature coronary artery disease (5). Login to comment

PMID: 15894595 [PubMed] Chassaing N et al: "Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations."

No. Sentence Comment

378 Interestingly, among the 49 different missense mutations in ABCC6 (42 previously published and seven new ones in the present study), the majority (43) replace critical amino acids in intracellular domains (seven and 19 mutations are located in I1424T R1459C 4220insAGAA 4318delA G1354R D1361N K1394N E1400K R1298X 410delC 418delG 3775delT R1275X R1221C D1238H W1223X Q1237X IVS26-1G→A R1114C R1114H R1114P S1121W M1127T T1130M R1138P R1138Q R1138W R1141X R1164X R765Q A766D Y768X A781V 2322delC IVS19-2delAG T364R R391G Q378X Q363_R373del 938_939insT 960delC IVS8+2delTG G199X Y227X 179_195del 179_187del G226R V74del Q749X IVS17-12delTT IVS14-5T→G IVS13-29T→A R600G V1298F G1299S T1301I G1302R A1303P S1307P R1314Q R1314W G1321S L1335P R1339C P1346S Q1347H R1030X F1048del R807Q V810M A820P 254delG L673P 1944_1966del 1995delG R518Q R518X K502M A455P G992R IVS21+1G→T G1203DF568SN411K C440G IVS25-3C→A 3544dupC Ex23_29del 30 Ex15del ABCC6del 252015105 Figure 10 Position of the mutations in the ABCC6 gene. Login to comment
379 Table 2 ABCC6 mutations Nucleotide variation Protein alteration Location (gene ) Location (protein) Reference Missense 676 GRA G226R Exon 7 CL 3 This study 1091 CRG T364R Exon 9 TS 7 63, 78 1171 ARG R391G Exon 9 CL 4 88 1233 TRG N411K Exon 10 CL 4 63, 90 1318 TRG C440G Exon 10 TS 8 63 1363 GRC A455P Exon 11 TS 9 86 1505 ART K502M Exon 12 CL 5 This study 1553 GRA R518Q Exon 12 CL 5 63, 86, 88, 90 1703 TRC F568S Exon 13 ECL 5 90 1798 CRT R600G Exon 14 CL 6 63 2018 TRC L673P Exon 16 NBF 1 90 2294 GRA R765Q Exon 18 NBF 1 87, 90 2297 CRA A766D Exon 18 NBF 1 88 2342 CRT A781V Exon 18 NBF 1 This study 2420 GRA R807Q Exon 19 NBF 1 This study 2428 GRA V810M Exon 19 NBF1 63 2458 GRC A820P Exon 19 NBF1 63 2965 GRC G992R Exon 22 ECL 6 This study 3340 CRT R1114C Exon 24 CL 8 63 3341 GRA R1114H Exon 24 CL 8 87 3341 GRC R1114P Exon 24 CL 8 90 3362 CRG S1121W Exon 24 CL 8 90 3380 CRT M1127T Exon 24 CL 8 63 3389 CRT T1130M Exon 24 CL 8 63, 87, 88 3412 CRT R1138W Exon 24 CL 8 17 3413 GRC R1138P Exon 24 CL 8 90 3413 GRA R1138Q Exon 24 CL 8 17, 63, 88, 90 3608 GRA G1203D Exon 25 TS17 90 3663 CRT R1221C Exon 26 COOH 87 3712 GRC D1238H Exon 26 COOH 88 3892 GRT V1298F Exon 28 NBF 2 90 3895 GRA G1299S Exon 28 NBF 2 This study 3902 CRT T1301I Exon 28 NBF 2 90 3904 GRA G1302R Exon 28 NBF 2 87, 90 3907 GRC A1303P Exon 28 NBF 2 87, 90 3919 TRC S1307P Exon 28 NBF 2 This study 3940 CRT R1314W Exon 28 NBF 2 90 3941 GRA R1314Q Exon 28 NBF 2 90 3961 GRA G1321S Exon 28 NBF 2 90 4004 TRC L1335P Exon 28 NBF 2 88 4015 CRT R1339C Exon 28 NBF 2 18, 63, 90 4036 CRT P1346S Exon 28 NBF 2 63 4041 GRC Q1347H Exon 28 NBF 2 90 4060 GRC G1354R Exon 29 NBF 2 78, 86 4081 GRA D1361N Exon 29 NBF 2 90 4182 GRT K1394N Exon 29 NBF 2 87 4198 GRA E1400K Exon 29 NBF 2 63, 88 4271 TRC I1424T Exon 30 NBF 2 90 4377 CRT R1459C Exon 30 NBF 2 87 Nonsense 595 CRT G199X Exon 5 89 681 CRG Y227X Exon 7 84 1132 CRT Q378X Exon 9 63, 78, 83 1552 CRT R518X Exon 12 63, 84, 88 2245 CRT Q749X Exon 17 87 2304 CRA Y768X Exon 18 90 3088 CRT R1030X Exon 23 63, 90 3421 CRT R1141X Exon 24 15, 17, 18, 63, 78, 85, 87, 88, 90 3490 CRT R1164X Exon 24 84, 85, 88 3668 GRA W1223X Exon 26 88 3709 CRT Q1237X Exon 26 90 3823 CRT R1275X Exon 27 63 4192 CRT R1398X Exon 29 90 Splicing alteration IVS8+2delTG Intron 8 This study IVS13-29 TRA Intron 13 This study IVS14-5 TRG Intron 14 This study IVS17-12delTT Intron 17 87 IVS18-2delAG Intron 17 63 IVS21+1 GRT Intron 21 86, 90 IVS25-3 CRA Intron 25 88 IVS26-1 GRA Intron 26 17, 63, 90 Insertion 938_939insT Frameshift Exon 8 90 3544dupC Frameshift Exon 25 63 4220insAGAA Frameshift Exon 30 15, 87 Small deletion 179_187del Frameshift Exon 2 78 179_195del Frameshift Exon 2 90 Pseudoxanthoma elasticum www.jmedgenet.com NBF1 and NBF2, respectively), four are located in transmembrane domains, and only two mutations have been identified in extracellular domains. Login to comment
383 Although most of the 90 pathogenic mutations have been identified in one or a limited number of families, two variants (Ex23_29del and R1141X) are recurrent mutations. Login to comment
384 The frequency of these two recurrent mutations differs according to the population studied: mutation Ex23_29del represents ,28% of the detected mutations in the US population and ,4% in the European population, whereas mutation R1141X represents ,4% of the detected mutations in the US population and ,28% in the European population.90 Furthermore, frequency of the R1141X differs between European countries (for example, 30% in the Dutch population,91 92 26% in Italian patients,63 and 13% in the French population88 ). Login to comment
385 A common founder effect was identified for mutation R1141X in French and Italian populations.63 88 We found that arginine codon 518 was a recurrently mutated amino acid in a cohort of 19 French families with PXE (11.5% of the detected mutations for each variant R518Q and R518X).88 These two mutations represent 19% of the mutations detected in the Italian population.63 In Japanese patients, neither R1141X nor Ex23_29del mutations were identified, whereas mutations 2542delG and Q378X account for 53% and 25%, respectively.93 In South African families of Afrikaaners, mutation R1339C represents more than half the mutations detected,28 with a common haplotype indicating a founder effect.27 28 These mutations are rarely identified in American or European populations.90 The detection rate in different studies varies from 0.55 to 0.83.63 87 88 90 Lack of mutation detection in some patients could reflect exonic deletions (for example, deletion of exon 15), splice site mutations distant from the coding sequence, mutations in the gene regulatory sequences, or investigation of patients with acquired PXE-like syndrome not related to ABCC6 mutations, such as seen in b thalassaemia and sickling syndromes (see below).94 95 Locus heterogeneity of PXE is unlikely, but cannot currently be ruled out. Login to comment
399 * In 2002, Trip et al reported that the prevalence of the sole R1141X mutation was significantly increased in young individuals with coronary artery disease (3.2%), but was also frequent in the general Dutch population.100 They identified eight heterozygous carriers for mutation R1141X among 1057 controls (0.76%). Login to comment
409 A few reports have emphasised the carriage of a sole ABCC6 mutation as a cardiovascular risk factor.70 100 102 In the study by Trip et al, mutation R1141X in ABCC6 appeared to be an independent risk factor for coronary heart disease in young people.100 This observation, if confirmed in other similar cohorts, could be of course of considerable concern for public health. Login to comment

PMID: 16086317 [PubMed] Miksch S et al: "Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6."

No. Sentence Comment

122 Initial Haplotype-Based Mutation Screening Strategy for Common Mutations and Deletions Initially all of the DNA samples were tested for the nonsense mutation c.3421C4T (p.R1141X) by restriction analysis of PCR products, since the c.3421C4T mutation causes loss of a Bsl I restriction site. Login to comment
246 PXE Mutations While most mutations are unique variants that represent the typical allelic heterogeneity of a recessive disease, we observed five mutations (p.R1141X [26%], p.I1000_S1403delW1404fsX1463 [11%], p.R1164X [5.3%], p.Q378X [3.5%], and c.278711G4T [3%]) at higher frequencies that accounted for almost 50% (exactly 48.8%) of the PXE mutations. Login to comment
251 The most frequently observed PXE mutation was p.R1141X. Login to comment
258 Hu et al. [2003a] reported p.R1141X in allelic linkage disequilibrium with the c.2490C4G polymorphism in his family cohort. Login to comment
260 This clearly demonstrates that while the p.R1141X mutation exhibits a founder effect, it has arisen independently in different population cohorts at least four times. Login to comment

PMID: 16127278 [PubMed] Schulz V et al: "Analysis of sequence variations in the ABCC6 gene among patients with abdominal aortic aneurysm and pseudoxanthoma elasticum."

No. Sentence Comment

105 The most common PXE mutation was the nonsense mutation p.R1141X which was observed in a homozygous form in 4 (7.4%) and in a heterozygous state in 20 (37.0%) PXE patients. Login to comment
116 The variations p.R1114C and p.G1311E occurred in a heterozygous form in 2 PXE patients, and RFLP or DHPLC analysis revealed that they were not present in our groups of healthy controls Exona Sequence variation Allele frequency AAA patients PXE patients PXE relatives blood donors 16 c.1964A>G (p.Q655R) 1 0 0 0/286 16 c.1990C>T (p.P664S) 0 0 0 1/286 16 c.1995delG (frameshift) 0 3 0 0/286 17 c.2171G>A (p.R724K) 3 1 1 2/254 17 c.2175A>T (p.V725V) 3 1 1 2/254 17 c.2224A>G (p.I742V) 3 1 1 2/254 i-17 IVS17+22T>G 1 0 0 0/254 18 c.2252T>A (p.M751K) 0 2 0 0/204 18 c.2278C>T (p.R760W) 0 1 0 0/204 18 c.2294G>A (p.R765Q) 0 3 0 0/204 24 c.3340C>T (p.R1114C) 0 1 0 0/400 24 c.3341G>A (p.R1114H) 0 1 0 0/400 24 c.3389C>T (p.T1130M) 0 2 0 0/400 24 c.3413G>A (p.R1138Q) 0 2 0 ND 24 c.3421C>T (p.R1141X) 0 28 9 1/1,820b i-24 IVS24+15G>A 1 0 0 ND 28 c.3902C>T (p.T1301I) 0 1 0 ND 28 c.3932G>A (p.G1311E) 0 1 0 0/400 28 c.3940C>T (p.R1314W) 0 1 0 ND 28 c.3941G>A (p.R1314Q) 0 1 1 ND i-28 IVS28+49C>T 59 ND ND ND i-28 IVS28-30C>T 48 ND ND ND 29 c.4182delG (frameshift) 0 3 0 0/400 i-29 IVS29+9G>A 5 ND ND ND 30 c.4209C>A (p.S1403R) 0 1 0 0/244 30 c.4254G>A (p.R1418R) 6 0 0 2/244 i-30 IVS30+11C>G 0 2 0 0/244 23-29 Ex23_Ex29del 0 5 3 ND i = intron; ND = not determined. Login to comment
123 DNA sequencing of all 31 ABCC6 exons showed that the first PXE patient was compound heterozygous for p.R1114C and the known PXE mutation c.1995delG in exon 16, whereas the second carried the new variant p.G1311E and the PXE-causing exon 24 mutation p.R1141X in a compound heterozygous state. Login to comment

PMID: 16133423 [PubMed] Gotting C et al: "Elevated xylosyltransferase I activities in pseudoxanthoma elasticum (PXE) patients as a marker of stimulated proteoglycan biosynthesis."

No. Sentence Comment

11 The occurrence of the frequent ABCC6 gene mutation c.3421C>T (R1141X) and the hypertension-associated genetic variants T174M and M235T in the angiotensinogen (AGT) gene were determined. Login to comment

PMID: 16135817 [PubMed] Klement JF et al: "Targeted ablation of the abcc6 gene results in ectopic mineralization of connective tissues."

No. Sentence Comment

45 In addition, it was recently suggested that a recurrent mutation in the ABCC6 gene, R1141X, which is frequently encountered in Caucasian populations, is associated with a significantly increased risk for cardiovascular disease (59). Login to comment

PMID: 16183260 [PubMed] Katona E et al: "Identification of a novel deletion in the ABCC6 gene leading to Pseudoxanthoma elasticum."

No. Sentence Comment

24 The most common mutations are R1141X and a deletion from exon 23 to 29, with the latter being present in 13% of PXE cases [5,9,11]. Login to comment

PMID: 16410789 [PubMed] Ringpfeil F et al: "Pseudoxanthoma elasticum is a recessive disease characterized by compound heterozygosity."

No. Sentence Comment

28 Five of the alleles harbored the recurrent R1141X mutation, which is prevalent in Caucasian populations, six of the alleles contained the R1138W mutation, and seven alleles harbored the deletion mutation del23-29, all of which have been previously reported in a number of families with PXE (Le Saux et al., 2001; Ringpfeil et al., 2001a; Uitto et al., 2001; Pulkkinen et al., 2002; Chassaing et al., 2004). Login to comment
30 In addition, a previously unpublished nonsense mutation W1324X was F568S/R1141X W1324X/R1141X Family 4 R1138W/R1138W R1138W/R1138W -/R1138W R1138W/- R1138W/- R1138W/- Family 6 R391G/R1138W R391G/R1138W Family 7 Family 2 Del23-29/W218C R391G/W218C Del23-29/W218C Del23-29/R391G W218C/- Del23-29/- Del23-29/- ? Login to comment
31 R1164Q/R518X R1164Q/R1164Q R1164Q/- -/- Family 5 Del23-29/R391G Del23-29/Del23-29 Family 3 R1141X/del23-29 R1141X/del23-29 Del23-29/- R1141X/T811M Family 1 Figure 1. Login to comment
40 In Family 1, the two affected daughters of a clinically unaffected mother and an affected father were compound heterozygotes (R1141X/del23-29), and the parents were carriers of the corresponding mutations. Login to comment
41 In addition, the father with asymptomatic angioid streaks, evidence of coronary artery disease, history of gastrointestinal bleeding, and positive skin biopsy, but no clinically obvious skin involvement, was compound heterozygous for R1141X and a novel missense mutation T811M. Login to comment
48 In Family 4, the two affected individuals, a father and a son, were compound heterozygotes, both for R1141X mutation in one allele, in combination with either F568S (father) or W1324X (son). Login to comment
53 However, probing the two most common mutations in ABCC6, namely R1141X and deletion of exons 23-29 in 254 control alleles of Caucasian origin, revealed no carriers (data not shown). Login to comment

PMID: 16543900 [PubMed] Le Saux O et al: "Serum factors from pseudoxanthoma elasticum patients alter elastic fiber formation in vitro."

No. Sentence Comment

177 21 Fibroblast U21 (M) PXE R1141X/R1141X ? Login to comment
178 Serum samples Control #1 (M) Normal wt/wt 45 Control #2 (M) Normal wt/wt 34 Control #3 (pool)1 Normal wt/wt Av. 68 Control #4 (pool)1 Normal wt/wt Av. 18 PXE 1 (F) PXE R391G/del23-29 50 PXE 2 (F) PXE IVS21+1 G4T/4104delC 51 PXE 3 (F) PXE IVS13-29 T4A/R1141X 41 PXE 4 (M) PXE ?/? Login to comment

PMID: 16604369 [PubMed] Bergen AA et al: "ABCC6 and pseudoxanthoma elasticum."

No. Sentence Comment

82 Two ABCC6 mutations, R1141X and del(ex23_29), occur very frequently, probably due to founder effects and genetic drift. Login to comment
83 R1141X accounts for up to 30% of mutations found in European populations [9, 18], but accounts for only 4% of the US PXE population. Login to comment
85 R1141X probably produces an instable ABCC6 mRNA which is rapidly degraded by nonsense mediated RNA decay [18, 29]. Login to comment
86 Finally, R1141X may be associated with premature coronary artery disease [48]. Login to comment

PMID: 16704654 [PubMed] Cattan D et al: "Early and severe amyloidosis in a patient with concurrent familial Mediterranean fever and pseudoxanthoma elasticum."

No. Sentence Comment

75 The fact that ABCC1 transports colchicine and decreases the activity of this drug could be one explanation for the poor efficacy of colchicine in preventing the extension of amyloidosis in our patient.26 A Dutch epidemiological study has demonstrated that R1141X, the most prevalent ABCC6 mutation in Europe, was not rare in the general population (0Æ8%).27 Accordingly, it can be speculated that ABCC6 Fig 4. Login to comment

PMID: 16854481 [PubMed] Kiec-Wilk B et al: "Acute myocardial infarction and a new ABCC6 mutation in a 16-year-old boy with pseudoxanthoma elasticum."

No. Sentence Comment

2 A 16-year-old survivor of acute myocardial infarction with 3-vessel coronary artery disease exhibited compound heterozygosity for the well-known nonsense mutation (c.3421C>T; R1141X) in exon 24 and a novel missense mutation (c.3662G>A; R1221H) in exon 26 of the ABCC6 gene. Login to comment
8 Interestingly, the most common disease-causing mutation in the European population (c.3421C>T; R1141X) predisposes to premature coronary artery disease in the absence of even mild ocular or dermatological PXE signs [4], whereas in PXE subjects abnormalities within the skin and eyes usually predominate and coronary symptoms are relatively rare generally occurring after the age of 35 [5]. Login to comment
22 The PXE boy exhibited compound heterozygosity for the well-recognized mutation (c.3421C>T; R1141X) in exon 24, and a novel one (c.3662G>A; R1221H) in exon 26 (Fig. 2). Login to comment
25 That a heterozygous form of the common R1141X nonsense mutation in exon 24 appears insufficient for the appearance of PXE, confirms earlier observations [5]. Login to comment
26 We suggest that the coincidence of the heterozygous R1141X mutation and a novel one (c.3662G>A; R1221H) in exon 26 on the other allele might have been responsible for PXE in the presented case. Login to comment

PMID: 17544787 [PubMed] Querques G et al: "Fundus autofluorescence."

No. Sentence Comment

26 Patients with premature coronary artery disease who carry the ABCC6 R1141X mutation have no pseudoxanthoma elasticum phenotype. Login to comment

PMID: 17617515 [PubMed] Pfendner EG et al: "Mutation detection in the ABCC6 gene and genotype-phenotype analysis in a large international case series affected by pseudoxanthoma elasticum."

No. Sentence Comment

187 Together with the recurrent R1141X and del23-29 mutations, these mutations accounted for 71.5% of the total individual mutations identified. Login to comment
200 Two recurrent mutations, R1141X and a large deletion of exons 23-29 (del23-29, p.A999_S1403del) have been described in a significant proportion of patients, leading to a mutation-detection strategy that first identifies the recurrent mutations by restriction-enzyme digestion, followed by sequencing of the remaining exons.39 In this study, we collected genotype data on 270 patients with PXE from 239 families and were able to characterise the phenotype in 198 of these patients to improve diagnosis, identify genotype-phenotype associations and facilitate genetic counselling of people at risk for PXE. Login to comment
211 Our mutation-detection strategy was based on: (1) identification of the recurrent mutations R1141X and del23-29 by restriction-enzyme digestion; (2) optimised denaturing high-performance liquid chromatography (dHPLC) scanning of PCR products corresponding to all exons in subjects in whom the two recurrent mutations were not identified on both alleles, followed by (3) sequencing of exons with altered dHPLC patterns; and (4) confirmation of novel mutations by restriction-enzyme digestion or resequencing. Login to comment
212 Screening for the recurrent mutations R1141X and del23-29 was performed as previously described.30 31 Conditions and primers for generating PCR products spanning all exons of the coding regions and flanking intronic sequences of the ABCC6 gene were identified for optimum dHPLC screening (supplementary table 1; available at http://jmg.bmj.com/supplemental). Login to comment
241 The two most common mutations were R1141X (29.3%, 92/316) and del23-29 (18%, 57/316). Login to comment
242 In all, 23 subjects (9.6%) were homozygous for either the R1141X (n = 11) or del23-29 (n = 2) or compound heterozygous (n = 10) for these two mutations. Login to comment
254 Collectively, the mutations in exons 24 and 28, including the common mutations R1141X and del 23-29, accounted for 71.5% of all the 316 mutations identified in this study (table 2), and the 11 most prevalent mutations (R1141X, del23-29, R1339C, R1164X, 2787+1GRT, G1302R, R1138Q, R1138W, Q378X, R1314W, R518Q) accounted for 70% (223 of 316) of the mutant alleles identified (table 2). Login to comment
288 The recurrent mutations R1141X and del23-29 were the most prevalent, consistent with previous reports. Login to comment
262 Genotype-phenotype correlations The comparison of subjects whose mutations would probably have resulted in no functional protein with those whose mutations would probably have resulted in some functional Table 2 Distinct mutations identified in the international case series of 271 patients with PXE Nucleotide change*À Predicted consequenceÀ Frequency (alleles) Exon-intron location Domain affected` Mutant alleles (%) References1 c.105delA p.S37fsX80 2 2 0.6 28 c.177-185del9 p.R60_Y62del 1 2 0.3 9, 28 c.179del12ins3 p. R60_W64del L60_R61ins 1 2 0.3 c.220-1gRc SJ 1 IVS 2 0.3 c.724gRt p.E242X 1 7 0.3 c.938insT FS 1 8 0.3 25 c.998+2delT SJ 1 IVS 8 0.3 2, 21 c.998+2del2 SJ 1 IVS 8 0.3 18 c.951cRg p.S317R 2 9 TM6 0.6 28 c.1087cRt p.Q363X 1 9 0.3 c.1091gRa p.T364R 1 9 TM7 0.3 9, 19, 21, 28 c.1132cRt p.Q378X 4 9 1.2 9, 17-19, 28, 37 c.1144cRt p.R382W 2 9 IC4 0.6 c.1171aRg p.R391G 3 9 IC4 0.9 9, 18, 28, 37 c.1176gRc p.K392N 1 9 IC4 0.3 c.1388tRa p.L463H 1 11 TM9 0.3 c.1484tRa p.L495H 1 12 IC5 0.3 28 c.1552cRt p.R518X 2 12 0.6 18, 19, 27, 28, 37 c.1553gRa p.R518Q 4 12 IC5 1.2 18, 19, 24, 28, 31 c.1603tRc p.S535P 1 12 TM10 0.3 c.1703tRc p.F568S 1 13 TM11 0.3 24 c.1798cRt p.R600C 1 14 TM11 0.3 c.1857insC FS 1 14 0.3 c.1987gRt p.G663C 1 16 NBF1 0.3 c.1999delG FS 1 16 0.3 c.2070+5GRA SJ 2 IVS 16 0.6 c.2093aRc p.Q698P 2 17 NBF1 0.6 c.2097gRt p.E699D 1 17 NBF1 0.3 c.2177tRc p.L726P 1 17 NBF1 0.3 c.2237ins10 FS 2 17 0.6 c.2252tRa p.M751K 1 18 NBF1 0.3 20, 37 c.2263gRa p.G755R 2 18 NBF1 0.6 c.2278cRt p.R760W 3 18 NBF1 0.9 20, 28, 32, 37 c.2294gRa p.R765Q 2 18 NBF1 0.6 20-22, 25, 28, 32, 37 c.2329gRa p.D777N 1 18 NBF1 0.3 c.2359gRt p.V787I 1 18 NBF1 0.3 c.2432cRt p.T811M 1 19 IC6 0.3 6 c.2643gRt p.R881S 1 20 IC6 0.3 c.2787+1GRT SJ 9 IVS 21 2.8 17, 20, 24, 28, 31, 37 c.2814cRg p.Y938X 1 22 0.3 c.2820insC FS 1 22 0.3 c.2831cRt p.T944I 1 22 TM12 0.3 c.2848gRa p.A950T 1 22 TM12 0.3 c.2974gRc p.G992R 1 22 TM13 0.3 2, 42 c.3340cRt p.R1114C 2 24 IC8 0.6 19, 28, 32, 37, 41 c.3389cRt p.T1130M 3 24 IC8 0.9 18, 19, 21, 22, 28, 30, 32, 37, 41 c.3398gRc p.G1133A 1 24 IC8 0.3 c.3412gRa p.R1138W 7 24 IC8 2.2 28, 30, 37 c.3413cRt p.R1138Q 7 24 IC8 2.2 18, 19, 24, 25, 28, 30, 32, 37, 41 c.3415gRa p.A1139T 2 24 IC8 0.6 c.3415gRa & c.2070+5GRA* p.A1139T & SJ 1 24, IVS 16 IC8 0.3 c.3415gRa & c.4335delG* p.A1139T & FS 1 24, 30 IC8 0.3 c.3421cRt p.R1141X 92 24 29.3 5, 9, 15,18, 19, 21, 22, 24, 28, 30-32, 33, 37, 41 c.3427cRt p.Q1143X 1 24 0.3 c.3490cRt p.R1164X 15 24 4.7 18, 27, 28, 31, 33 c.3491gRa p.R1164Q 1 24 IC8 0.3 28 c.3661cRt p.R1221C 1 26 IC9 0.3 21, 22, 28, 29 c.3662gRa p.R1221H 2 26 IC9 0.6 40 c.3676cRa p.L1226I 1 26 IC9 0.3 c.3722gRa p.W1241X 2 26 0.6 c.3774insC FS 2 27 0.6 c.3775delT p.G1259fsX1272 3 27 0.9 15, 25, 28, 41 c.3880-3882del p.K1294del 1 27 0.3 c.3883-5GRA SJ 1 IVS 27 0.3 c.3892gRt p.V1298F 1 28 NBF2 0.3 25 c.3904gRa p.G1302R 7 28 NBF2 2.2 21, 22, 25, 28 c.3907gRc p.A1303P 1 28 NBF2 0.3 21, 22, 25, 28 c.3912delG FS 1 28 0.3 28 c.3940cRt p.R1314W 4 28 NBF2 1.2 24, 25, 32, 36 c.3941gRa p.R1314Q 1 28 NBF2 0.3 25, 28, 32, 36, 41 c.4004tRa p.L1335Q 1 28 NBF2 0.3 c.4015cRt p.R1339C 16 28 NBF2 5.0 19, 25, 28, 33 c.4016gRa p.R1339H 2 28 NBF2 0.6 c.4025tRc p.I1342T 1 28 NBF2 0.3 protein did not yield significant differences. Login to comment

PMID: 17880583 [PubMed] Bowen AR et al: "Pseudoxanthoma elasticum-like fibers in the inflamed skin of patients without pseudoxanthoma elasticum."

No. Sentence Comment

42 The analysis of the c.3421C.T (R1141X) mutation through rapid-cycle PCR and hybridization analysis with the LightCycler (Roche, Penzberg, Germany) was performed as described previously,7 with the following modifications: (1) an improved primer mixture containing the oligonucleotides E24LCU (5#-CTCCCATCCATCCTTCT-3#), E24LCL (5#-CCTCGCTACCATACAATATGA-3#) and Ex24LCL_T (5#-CCTCTCTACCATACAA- TATGA-3#) in equal amounts was used in the assay to improve genotyping reliability in patients carrying the intronic polymorphism IVS24 1 83C.A in the ABCC6 gene, (2) 3 ml of DNA isolated from paraffin-embedded tissues was used in the reaction mixture (20 ml) and (3) amplification was performed using 50 cycles of 95°C for 1 s, 56°C for 10 s and 72°C for 20 s to increase signal intensity. Login to comment

PMID: 18157818 [PubMed] Vanakker OM et al: "Novel clinico-molecular insights in pseudoxanthoma elasticum provide an efficient molecular screening method and a comprehensive diagnostic flowchart."

No. Sentence Comment

127 12-001(II-1) C F I:1 I:2 II:1 II:2 II:3II:4 III:1 III:2 II:5 III:3 III:4 R1141X/ WT R1141X/ WT R1141X/ WT R1141X/ WT R1141X/ WT R1141X/ R1141X D E A B R1141X/ R1141X R1141X/ WT 12-002(II-3) Table 2. Prevalence of the Cutaneous (A) and Ocular (B) Manifestations of PXE in This Study at Initial Presentation and at Last Consultation Initial presentation Last consultation A. Login to comment
28 One is the nonsense mutation c.3421C>T (p.R1141X), which, in a homozygous state, leads to complete loss of ABCC6 function and is more frequent among the European population [Chassaing et al., 2005]. Login to comment
78 Mutations were most frequently located in exons 24 (47%), mainly due to the p.R1141X mutation, 18 (8%), 28 (7%) and 29 (5%). Login to comment
80 The nonsense mutation c.3421C>T (p.R1141X) in exon 24 was most frequently found (31/76 alleles or 41%), both in homozygous (52%) and compound heterozygous (43%) state. Login to comment
83 Genotype and Phenotype of 42 Belgian PXE Patients Patient S e x Age/Clinical score at initial presentation Age/Clinical score at most recent follow-up Mutations* Allele 1 Allele 2 01-001 F 52 - S0, E2 65 - S0, E3, HT p.R1141X c.3421C>T p.R760Q c.2279G>A 02-001 M 18 - S1, E2, VR-I 18 - S1, E2, VR-I p.R1141X c.3421C>T p.R1141X c.3421C>T 03-001 F 59 - S1, E4 75 - S1, E4, HT, IC, VR-I p.R1141X c.3421C>T p.N793L c.2379C>G 04-001 F 36 - S3, E2 36 - S3, E2 p.N466Y c.1396A>T p.R1339H c.4016G>A 05-001 F 26 - S1, E4 43 - S3, E4, VR-I p.R1141X c.3421C>T p.T364M c.1091C>T 06-001 F 36 - S2, E4 44 - S2, E4, P p.A1303P c.3907G>C None found - 07-001 M 48 - S1, E2, HT 58 - S1, E4, HT p.R1141X c.3421C>T p.R1141X c.3421C>T 08-001 F 26 - S1, E0 44 - S2, E2 p.R1141X c.3421C>T p.R760Q c.2279G>A 09-001 M 49 - S0, E3, P, GIB 65 - S2, E4, P, HT, VR-I, GIB p.A1303P c.3907G>C None found - 10-001 F 46 - S1, E2 63 - S3, E4, HT, AP,VR-I p.R1141X c.3421C>T p.R1141X c.3421C>T 11-001 M 25 - S1, E2, GIB 37 - S1, E3, GIB p.R1141X c.3421C>T None found - 12-001 F 52 - S1, E4, CI, HT, VR-I 52 - S1, E4, IC, HT, VR-I p.R1141X c.3421C>T p.R1141X c.3421C>T 12-002 F 40 - S1, E2, HT, MVP, VR-I 40 - S1, E2, HT, MVP, VR-I p.R1141X c.3421C>T p.R1141X c.3421C>T 13-001 F 65 - S0, E2 80 - S0, E2, P, VR-I p.R1141X c.3421C>T p.R1141X c.3421C>T 13-002 F 57 - S3, E4 73 - S3, E4, HT, CI, VR-I p.R1141X c.3421C>T p.R1141X c.3421C>T 14-001 F 23 - S1, E2 27 - S1, E2 p.S398R c.1194C>G - c.3364delT 15-001 F 27 - S1, E2 27 - S1, E2 p.R1138W c.3412C>T p.R1221H c.3662G>A 16-001 M 51 - S2, E2 54 - S2, E2 p.R1141X c.3421C>T p.R1141X c.3421C>T 17-001 M 42 - S1, E3, IC 58 - S1, E3, IC Del23-29 - p.R518Q c.1553G>A 18-001 M 63 - S1, E4 63 - S1, E4 p.E1400K c.4198G>A None found - 19-001 F 34 - S2, E2 50 - S2, E2 p.A1303P c.3907G>C p.R1398X c.4192C>T 20-001 F 52 - S2, E2, HT, IC, GIB 68 - S2, E4, HT, IC, GIB p.R1141X c.3421C>T None found - 21-001 M 20 - S1, E2 26 - S1, E2 p.R1141X c.3421C>T p.R1141X c.3421C>T 22-001 M 53 - S2, E2, IC, AP 69 - S2, E2, HT, IC, AP p.M751K c.2252T>A p.R1164Q c.3491G>A 23-001 F 20 - S1, E2 27 - S1, E2, P, VR-I p.G666V c.1996G>T - c.1868-5T>G 24-001 M 54 - S1, E2 57 - S1, E2 p.T500P c.1498A>C p.E521D c.1563G>C 25-001 F 50 - S1, E3, HT, MI 57 - S2, E3, HT, MI p.R1141X c.3421C>T p.R1141X c.3421C>T 26-001 M 52 - S2, E4, HT 68 - S2, E4, HT, CI p.M751K c.2252T>A Del23-29 - 27-001 F 61 - S3, E4 68 - S3, E4, P, CI, AP p.R1141X c.3421C>T - c.4104delC Allele 2 28-001 F 31 - S1, E2 32 - S1, E2 - c.1674DelC p.R765W c.2293C>T Patient S e x Age/Clinical score at initial presentation Age/Clinical score at most recent follow-up Mutations* Allele 1 Allele 2 29-001 M 30 - S1, E3 32 - S1, E3 p.E125K c.373G>A p.L1025P c.3074T>C 30-001 M 65 - S0, E2, HT, CI, MI 66 - S0, E2, HT, CI, MI p.G1405S c.4213G>A None found - 31-001 F 38 - S1, E4 39 - S1, E4 p.R1141X c.3421C>T Del23-29 - 32-001 M 22 - S1, E2 36 - S1, E2 p.R1141X c.3421C>T p.R518Q c.1553G>A 33-001 F 45 - S2, E3, P 61 - S2, E3, P, VR-II p.R1141X c.3421C>T p.R1141X c.3421C>T 34-001 F 65 - S1, E4, HT 81 - S1, E4, HT, AP p.R1141X c.3421C>T p.T1301I c.3902C>T 35-001 F 62 - S2, E2 78 - S2, E2, HT - c.175_179del p.G1354R c.4060G>C 35-002 F 58 - S2, E2 74 - S2, E4 - c.175_179del p.G1354R c.4060G>C 35-003 M 67 - S2, E2 79 - S2, E3, HT, VR-I - c.175_179del p.G1354R c.4060G>C 36-001 M 53 - S1, E4 59 - S1, E4, HT, AP p.R1114H c.3341G>A p.Q1237X c.3709C>T 37-001 M 18 - S3, E2 18 - S3, E2 p.Q981H c.2943G>T - c.3507-3C>A 38-001 F 27 - S1, E2 27 - S1, E2 p.G1263R c.3787G>A - c.4182delG Table 1 represents the sex of all patients (M = male; F= female) and the age (in years - italics), respectively at initial presentation and last follow-up. Login to comment
141 Especially in patients homozygous for the p.R1141X mutation - previously associated with a more severe phenotype [Hu et al., 2003]-, no significant difference with patients with either one or no nonsense mutation was observed. Login to comment
145 An initial analysis can be limited to the latter four exons (including p.R1141X) and the Del23-29 with a direct sequencing based approach. Login to comment

PMID: 18253096 [PubMed] Plomp AS et al: "ABCC6 mutations in pseudoxanthoma elasticum: an update including eight novel ones."

No. Sentence Comment

265 Analysis of the frequent R1141X mutation in the ABCC6 gene in pseudoxanthoma elasticum. Login to comment

PMID: 18800149 [PubMed] Li Q et al: "Mutations in the GGCX and ABCC6 genes in a family with pseudoxanthoma elasticum-like phenotypes."

No. Sentence Comment

31 Patient (III-3) Patient (III-3) Patient (III-3) Patient (II-2) Patient (II-3) Patient (II-3) a b c d e f g Skin Coagulation GGCX ABCC6 GGCX ABCC6 V255M S300F R1141X V255M S300F R1141X 1 1 2 3 4 3 2 21 5 II I III - -+ + + - - - - + + + + + + + + + Figure 1. Login to comment
3 The proband`s mother and aunt, also manifesting with PXE-like skin changes, were heterozygous carriers of a missense mutation (p.V255M) in GGCX and a null mutation (p.R1141X) in the ABCC6 gene, suggesting digenic nature of their skin findings. Login to comment
41 The recurrent mutation, p.R1141X, which is particularly prevalent (about 30% of all detected mutations in PXE patients of the European extraction; Pfendner et al., 2007) was found in the DNA from the father, mother, the maternal aunt and the younger brother, but not in the proband herself or her sister (Figures 1g and 3a). Login to comment
64 The latter individuals were also carriers of the ABCC6 nonsense mutation p.R1141X. Login to comment
65 Specifically, the mother and her twin sister were heterozygous for the GGCX missense mutation p.V255M and the ABCC6 nonsense mutation p.R1141X, suggesting digenic inheritance of their cutaneous findings. Login to comment
66 However, the proband`s younger brother and father were heterozygous carriers of the p.S300F mutation in the GGCX gene although they also carried the p.R1141X mutation in the ABCC6 gene; they did not display any signs of cutaneous findings or hematologic disorder. Login to comment
67 Assay of c-glutamyl carboxylase activity Previous studies have clearly demonstrated that the p.R1141X mutation in the ABCC6 gene in heterozygous carriers does not cause PXE (Wegman et al., 2005; Pfendner et al., 2007). Login to comment
77 (a) Identification of the recurrent nonsense mutation p.R1141X in the ABCC6 gene. Login to comment
131 The recurrent mutation p.R1141X was found in the DNA from the father, mother, the maternal aunt and the younger brother, but not in the proband herself or her sister. Login to comment
140 The latter individuals were also carriers of the ABCC6 nonsense mutation p.R1141X. Login to comment
141 It should be noted that the mother and her twin sister were heterozygous for one of the GGCX missense mutation p.V255M and one ABCC6 nonsense mutation p.R1141X, suggesting digenic inheritance of their cutaneous findings. Login to comment
144 It should be noted, however, that in a cohort of 4300 families with PXE analyzed in our laboratory for mutations in the ABCC6 gene, five individuals were heterozygous carriers of a mutation (p.R1141X) in one ABCC6 allele only, yet none of them carried a mutation in the GGCX gene (unpublished). Login to comment
163 Mutations in the ABCC6 gene have been shown to cause PXE, an autosomal recessive disorder (Ringpfeil et al., 2006), but heterozygous carriers of mutations, such as p.R1141X detected in the proband`s mother and aunt, are asymptomatic (Wegman et al., 2005; Pfendner et al., 2007). Login to comment
170 These two individuals were heterozygous carriers of p.R1141X mutation in ABCC6 and p.V255M in GGCX. Login to comment
171 As heterozygous carriers of p.R1141X in ABCC6 alone do not manifest PXE and GGCX mutations with respect to coagulation disorder are recessive, these findings suggest that the skin phenotype in these two individuals may be because of digenic inheritance. Login to comment
173 The reasons for the fact that the proband`s father and her brother were heterozygous carriers of mutations in the ABCC6 gene (p.R1141X) and the GGCX gene (p.S300F) yet did not display any cutaneous findings are not clear. Login to comment

PMID: 18936737 [PubMed] Hendig D et al: "Gene expression profiling of ABC transporters in dermal fibroblasts of pseudoxanthoma elasticum patients identifies new candidates involved in PXE pathogenesis."

No. Sentence Comment

305 Hu X, Peek R, Plomp A, et al. Analysis of the frequent R1141X mutation in the ABCC6 gene in pseudoxanthoma elasticum. Login to comment
62 Table 1 Main characteristics of dermal fibroblasts derived from PXE patients and healthy controls used in the present study Sample ID Gender Agea Biopsy source ABCC6 genotypeb Statusc Age at disease onseta Number of involved organs PXE patients P60F Female 58 Axilla c.37-1G4A (SSM) c.37-1G4A (SSM) hm 56 3 P229F Female 50 NA c.1171A4G (p.R391G) c.1208C4A (p.A413N) c.2252T4A (p.M751K) cht NA NA P265F Female 62 Cervix c.1132C4T (p.Q378X) c.3421C4T (p.R1141X) cht 16 3 P3M Male 57 Cervix c.3421C4T (p.R1141X) c.3883-6G4A (SSM) cht 46 5 P128M Male 51 Cervix c.3769_3770insC (p.L1259fsX1277) c.3769_3770insC (p.L1259fsX1277) hm 48 3 P308M Male 42 NA c.3421C4T (p.R1141X) c.-90ins14 (c)ht NA NA P341M Male 41 NA c.1552C4T (p.R518X) ND ht NA NA Healthy controls F37A Female 37 Abdomen - - - wt - - F42A Female 42 Abdomen - - - wt - - F52C Female 52 Cheek - - - wt - - M2FS Male 2 Foreskin - - - wt - - M45D Male 45 Face - - - wt - - M56D Male 56 Face - - - wt - - hm, homozygote; cht, compound heterozygote; ht, heterozygote; wt, wild type; SSM, splice site mutation; NA, not applicable; ND, nondetected. Login to comment

PMID: 19298904 [PubMed] Finger RP et al: "Pseudoxanthoma elasticum: genetics, clinical manifestations and therapeutic approaches."

No. Sentence Comment

21 The exact prevalence is unknown, with a recent estimated range between 1:25,000 and 1:100,000.21 Prevalence seems to be higher in South Africa compared to other regions, possibly due to a founder effect.28 Applying the Hardy-Weinberg equilibrium, this leads to a frequency of 1.25% heterozygotes (1:80).21 In 2002, a prevalence of 3% of heterozygous carriers of the R1141X mutation of the ABCC6 gene was reported in a Dutch population of young patients affected by coronary heart disease. Login to comment

PMID: 19339160 [PubMed] Ramsay M et al: "Spectrum of genetic variation at the ABCC6 locus in South Africans: Pseudoxanthoma elasticum patients and healthy individuals."

No. Sentence Comment

80 Exons 12, 18 and 24 were PCR amplified and sequenced to detect the R518Q, Y768X, R1141X and R1138Q mutations and the common del23-29 mutation was detected as previously described [16]. Login to comment
98 The next three more common mutations are R1141X (0.09), Y768X (0.08) and R1138Q (0.06). Login to comment
121 of alleles with mutation Frequency R1339C c.4015C>T 28 NBF2 18 0.375 21 0.447 0.411 (39) [30-32] R1138Q c.3413G>A 24 CL8 5 0.104 1 0.021 0.063 (6) [3,7,32] Y768X c.2304C>A 18 NBF1 5 0.104 3 0.064 0.084 (8) [31] R1141X c.3421C>T 24 CL8 4 0.083 5 0.106 0.095 (9) [3,6,13] R518Q c.1553G>A 12 CL5 2 0.042 1 0.021 0.032 (3) [31-33] Deletion ABCC6del23-29 23-29 - 1 0.021 2 0.043 0.032 (3) [6,16,31,32] L1335P c.4004T>C 28 NBF2 2 0.042 - - Other = 0.063 (6) [3] G1302R c.3904G>A 28 NBF2 1 0.021 - - [31] L726P c.2177T>C 17 NBF1 1 0.021 - - This Study Frameshift c.3775delT 27 CL9 1 0.021 - - [6] Frameshift c.4104delC 29 NBF2 1 0.021 - - [31] Unknown - - - 7 0.146 14 0.298 0.221 (21) - Total 48 47 Mutation detection rate 0.855 0.702 0.717 a ''Coloured``, black and Indian patients are excluded from the table because of the small sample size. Login to comment
145 Mutation Afrikaans-speakersa English-speakersa No. Frequency No. Frequency R1339C 34 0.54 4 0.14 R1138Q 5 0.08 1 0.04 Y768X 5 0.08 3 0.11 R1141X 5 0.08 4 0.14 R518Q 1 0.02 2 0.07 del23-29 0 - 3 0.11 Other 0 - 4 0.14 Unknown 13 0.21 7 0.25 Total no. alleles 63 28 a Only 2 families were bilingual Afrikaans/English speaking and not included in this table. Login to comment
160 Three further mutations have frequencies above 0.06, namely R1138Q, Y768X and R1141X. Login to comment
195 It detects 79.2% of the PXE mutations in white South African patients including: R1339C, R1138Q, Y768X, R1141X, R518Q, del23-29, L1335P and G1302R (calculated according to detection Strategy 1, Table 1). Login to comment

PMID: 19929409 [PubMed] Koblos G et al: "The R1141X loss-of-function mutation of the ABCC6 gene is a strong genetic risk factor for coronary artery disease."

No. Sentence Comment

0 The R1141X Loss-of-Function Mutation of the ABCC6 Gene Is a Strong Genetic Risk Factor for Coronary Artery Disease Gabriella Ko¨blo¨s,1 Hajnalka Andrikovics,2 Zolta´n Proha´szka,3 Attila Tordai,2 Andra´s Va´radi,1 and Tama´s Ara´nyi1 Loss-of-function mutations of ABCC6 cause pseudoxanthoma elasticum (PXE). Login to comment
13 The most frequent mutation, accounting for 20-30% of all mutations, is the c.3421C>T nucleotide change leading to the R1141X nonsense mutation (Pfendner et al., 2008). Login to comment
32 Indeed, a strong correlation between a rare sequence variant of the ABCC6 gene (c.3421C>T leading to the R1141X nonsense mutation) and CAD has been demonstrated in a Dutch cohort (Trip et al., 2002). Login to comment
37 We analyzed the allele frequency (AF) of the c.3421C > T (R1141X) mutation in healthy blood donors, patients with CAD, and patients suffering from ischemic stroke. Login to comment
61 The following equation was used to calculate the prevalence of PXE (P) in the control population: P ¼ 1=(AF · 4 · 0:01)2 (1) The maximal and minimal prevalence (Pm) were calculated by taking into account the 95% CI of AF determined in the various studies: Pm ¼ 1=[(AF Æ 95% CI · 0:01) · 4]2 (2) Results and Discussion Determination of the frequency of R1141X in the control population Before investigating the eventual association of the R1141X loss-of-function mutation of ABCC6 with CAD or stroke, we determined the frequency of this allele in our control population consisting of 749 healthy blood donors. Login to comment
62 This seemed to be important, since the two existing studies on the AF of the R1141X mutation in healthy Caucasians reported significantly different results ( p ¼ 0.028; Table 1) (Trip et al., 2002; Gotting et al., 2004). Login to comment
65 The corresponding frequency of the R1141X allele is almost identical to the German cohort (Gotting et al., 2004) ( p ¼ 0.495). Login to comment
68 Determination of the frequency of R1141X in patients with ischemic stroke Various anecdotal reports exist about a higher incidence of stroke in PXE patients than in unaffected individuals. Login to comment
73 This frequency of heterozygotes among stroke patients is not significantly different from controls ( p ¼ 0.44); thus, the carrier status of R1141X mutation of the ABCC6 gene is not a risk factor for stroke. Login to comment
77 Determination of the frequency of R1141X in patients with CAD Trip et al. found that the carrier status for the R1141X mutation of the ABCC6 gene is a risk factor for the development of CAD. Login to comment
79 We determined the number of heterozygotes among the CAD patients and found five individuals carrying the R1141X mutation (Table 2). Login to comment
88 Accordingly, Trip et al. found a significantly higher R1141X AF in the CAD group than we did. Login to comment
90 Nevertheless, both this and the previous study demonstrated a very strong correlation between CAD and the haploinsufficiency of ABCC6 due to the R1141X mutation. Login to comment
95 Based on the frequency of ABCC6 R1141X allele, approximately 0.5% of the control Caucasian population is a carrier of a loss-of-function mutation concerning several hundred thousands of individuals. Login to comment
97 Frequency of R1141X Heterozygotes in the Control Groups of the Three Different Studies Population Dutch German Hungarian n 1057 910 749 Carriers 8 1 1 AF 95% CI 0.38 Æ 0.27% 0.06 Æ 0.11% 0.07 Æ 0.13% n, cohort size; AF, allele frequency; CI, confidence interval. Login to comment
99 Frequency of R1141X Heterozygotes in the Stroke, Control, and Coronary Artery Disease Groups Cohort Stroke Blood donors Coronary artery disease n 363 749 361 Carriers 1 1 5 AF 95% CI 0.14 Æ 0.28% 0.07 Æ 0.13% 0.69 Æ 0.62% ABCC6 AND CORONARY ARTERY DISEASE screening would not be appropriate, but as most of them are relatives of PXE patients they can easily be identified. Login to comment

PMID: 20075945 [PubMed] Costrop LM et al: "Novel deletions causing pseudoxanthoma elasticum underscore the genomic instability of the ABCC6 region."

No. Sentence Comment

97 Surprisingly, we identified deletions removing the region of exon 24 in two of these patients, indicating that a non-negligible proportion of patients with R1141X were in fact compound heterozygous. Login to comment
13 Two of these mutations are particularly prevalent, a deletion of exon 23-29 (del23-29) and p.R1141X (c.3421C4T).6-8 To date, only 16 different large ABCC6 deletions (entire exons, whole gene deletions) have been identified in PXE patients.7,9-14 Nevertheless, ABCC6 is extremely prone to genomic rearrangements because of the high content of repetitive elements in all introns and in the genomic sequences surrounding the gene.14 We hypothesized that because of the documented instability of the ABCC6 genomic region, the unidentified mutant alleles remaining after direct sequencing and screening for the recurrent exon 23-29 deletion, may consist of deletions and/or insertions. In this study, we aimed to screen for the presence of such deletions and/or insertions using the multiplex ligation-dependent probe amplification (MLPA) technique. Login to comment
83 Finally, we performed MLPA analysis in eight patients with a previously identified apparently homozygous p.R1141X mutation (exon 24) to verify whether the subjects were indeed homozygotes Patient 3 1 0.5 0 -0.5 -1 -1.5 Patient 13 1 0.5 0 -0.5 -1 -1.5 0Mb Patient 26 1 0.5 0 -0.5 -1 -1.5 Patient 34 1 0.5 0 -0.5 -1 -1.5 EXON27 EXON26 EXON25 EXON24 EXON23 16.16Mb 16.16Mb 16.16Mb 16.16Mb 16.16Mb 16.17Mb 16.17Mb 16.17Mb 9.87Mb 19.74Mb 29.61Mb 0Mb 9.87Mb 19.74Mb 29.61Mb 0Mb Chr.16 9.87Mb 19.74Mb 29.61Mb p.13.3 p.13.2 p.13.12 p.12.3 p.12.1 p.11.1 p.13.3 p.13.2 p.13.12 p.12.3 p.12.1 p.11.1p.13.3 p.13.2 p.13.12 p.12.3 p.12.1 p.11.1 Chr.16 Chr.16 Chr.16 Patient 32 0.5 0 -0.5 1 16146Kb EXON31 EXON30Chr.16 16148Kb 16150Kb 16151Kb 16153Kb 16156Kb -1 a b Figure 2 Array CGH based results. Login to comment

PMID: 20491760 [PubMed] Li Q et al: "Mutation analysis (ABCC6) in a family with pseudoxanthoma elasticum: presymptomatic testing with prognostic implications."

No. Sentence Comment

55 9 Trip MD, Smulders YM, Wegman JJ et al. Frequent mutation in the ABCC6 gene (R1141X) is associated with a strong increase in the prevalence of coronary artery disease. Login to comment
57 10 Ko¨blo¨s G, Andrikovics H, Proha´szka Z et al. The R1141X loss-of- function mutation of the ABCC6 gene is a strong genetic risk factor for coronary artery disease. Login to comment

PMID: 21167005 [PubMed] Larusso J et al: "Pseudoxanthoma elasticum: a streamlined, ethnicity-based mutation detection strategy."

No. Sentence Comment

43 In our PXE cohort, the recurring nonsense mutation p.R1141X was present in all five ethnic groups, with the exception of Asian, representing 15.4% of French Canadian, 19.2% of Mediterranean, 20.5% of Northern European, and 36.4% of Scandinavian mutations; overall it occurred in 22.9% (32/140) of all the alleles examined. The high frequency of this mutation in the Mediterranean and Northern European population may be explained by a founder effect.18 The allele p.R1141X was found to share a common haplotype identical by descent in French19 and Italian patients.20 In three different studies examining German,21 Italian,20 and French PXE patients,19 R1141X was found to be the most frequent mutation. Login to comment
20 The frequent p.R1141X mutation was distributed widely across Europe, while deletion of exons 23-29 (del23-29) was encountered in Northern Europe and in Northern Mediterranean countries. Login to comment
42 A total of eight recurrent mutations were distinguished in the cohort, including nonsense (p.Q378X and p.R1141X), missense (p.R1138W and p.R1339C), splice site (3736-1G/A, 2787 + 1G/T), frameshift (2542 delG), and multiexon deletion (del exon 23-29). Login to comment
44 p.R1141X segregated in a compound heterozygous mode in 50% of French Canadians, 80% in Mediterranean, 75% in Northern Europeans, and in 33.3% of Scandinavians. Login to comment
46 The p.R1141X mutation can be detected by BsiYI restriction enzyme digestion and agarose gel electrophoresis, and confirmation can be attained by sequencing. Login to comment
64 Analysis of mutations found in Japanese patients by Noji et al.,22 combined with our study, suggested that neither the nonsense mutation p.R1141X nor the large deletion ABCC6 del 23-29 are frequent in this ethnicity group. Login to comment
83 17, 23, and24), suggest future screening strategies that incorporate the patient`s ethnic background.Suchdiagnosticstrategyshouldbeespeciallyefficient for the European and Mediterranean populations in which a number of PXE mutations occur frequently (p.R1141X and del exons 23-29). Login to comment

PMID: 16384891 [PubMed] Hendig D et al: "Role of serum fetuin-A, a major inhibitor of systemic calcification, in pseudoxanthoma elasticum."

No. Sentence Comment

4 The occurrences of the frequent ABCC6 gene mutations c.3421C>T (p.R1141X) and c.EX23_ EX29del were also assessed. Login to comment

PMID: 16763870 [PubMed] Ladewig MS et al: "[Pseudoxanthoma elasticum]."

No. Sentence Comment

272 Internetadressen PXE-Selbsthilfegruppe Deutschland : http://www.pxe-groenblad.de PXE International: http://www.pxe.org Tabelle 5 PXE verursachende Mutationen imabcc6-Gen Klassifikation Lokalisation Gen Protein Missense Exon 9 Exon 9 Exon 10 Exon 10 Exon 11 Exon 12 Exon 13 Exon 14 Exon 16 Exon 18 Exon 18 Exon 18 Exon 18 Exon 19 Exon 19 Exon 19 Exon 22 Exon 24 Exon 24 Exon 24 Exon 24 Exon 24 Exon 24 Exon 24 Exon 24 Exon 24 Exon 25 Exon 26 Exon 26 Exon 26 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 28 Exon 29 Exon 29 Exon 29 Exon 29 Exon 29 Exon 30 Exon 30 Exon 30 c.1091CaG c.1171AaG c.1233TaG c.1318TaG c.1363GaC c.1553GaA c.1703TaC c.1798CaT c.2018TaC c.2252TaA c.2278CaT c.2294GaA c.2297CaA c.2428GaA c.2458GaC c.2552TaC c.2855TaG c.3340CaT c.3341GaA c.3341GaC c.3362CaG c.3380CaT c.3389CaT c.3412CaT c.3413GaA c.3413GaC c.3608GaA c.3661CaT c.3712GaC c.3715TaC c.3892GaT c.3902CaT c.3904GaA c.3907GaC c.3932GaA c.3940CaT c.3941GaA c.3961GaA c.3976GaA c.4004TaC c.4015CaT c.4036CaT c.4041GaC c.4060GaC c.4069CaT c.4081GaA c.4182GaT c.4198GaA c.4209CaA c.4271TaC c.4377CaT p.T364R p.R391G p.N411K p.C440G p.A455P p.R518Q p.F568S p.R600G p.L673P p.M751K p.R760W p.R765Q p.A766D p.V810M p.A820P p.L851P p.F952C p.R1114C p.R1114H p.R1114P p.S1121W p.M1127T p.T1130M p.R1138W p.R1138Q p.R1138P p.G1203D p.R1221C p.D1238H p.Y1239H p.V1298F p.T1301I p.G1302R p.A1303P p.G1311E p.R1314W p.R1314Q p.G1321S p.D1326N p.L1335P p.R1339C p.P1346S p.Q1347H p.G1354R p.R1357W p.D1361N p.K1394N p.E1400K p.S1403R p.I1424T p.R1459C Klassifikation Lokalisation Gen Protein Nonsense Exon 9 Exon 12 Exon 17 Exon 18 Exon 23 Exon 24 Exon 24 Exon 26 Exon 26 Exon 27 Exon 29 c.1132CaT c.1552CaT c.2247CaT c.2304CaA c.3088CaT c.3421CaT c.3490CaT c.3668GaA c.3709CaT c.3823CaT c.4192CaT p.Q378X p.R518X p.Q749X p.Y768X p.R1030X p.R1141X p.R1164X p.W1223X p.Q1237X p.R1275X p.R1398X Spleißstellen Intron 21 Intron 25 Intron 26 c.2787+1GaT c.3634-3CaA c.3736-1GaA Insertion Exon 8 Exon 25 Exon 30 c.938-939insT c.3544dupC c.4220insAGAA Deletion Exon 2 Exon 2 Exon 3 Exon 8 Exon 9 Exon 16 Exon 16 Exon 18 Exon 19 Exon 22 Exon 27 Exon 29 Exon 29 Exon 30 Exon 31 c.179del9 c.179-195del c.220-222del c.960delC c.1088-1120del c.1944del22 c.1995delG c.2322delC c.2542delG c.2835-2850del16 c.3775delT c.4101delC c.4182delG c.4318delA c.4434delA Intragenische Deletion Exon 15 Exon 18 Exon 23-29 delEx15 delEx18 delEx23-29 Intergenische Deletion ABCC6 delABCC6 Fazit für die Praxis Eine spezifische Behandlung der Grunderkrankung ist nicht bekannt. Login to comment

PMID: 16835894 [PubMed] Schulz V et al: "Mutational analysis of the ABCC6 gene and the proximal ABCC6 gene promoter in German patients with pseudoxanthoma elasticum (PXE)."

No. Sentence Comment

8 Frequent alterations were the PXE-mutations p.R1141X, Ex23,_Ex29del, and c.2787+1G>T. Login to comment
72 The most common PXE mutations were the nonsense mutation p.R1141X, the splice site mutation c.2787+1G>T and the large deletion Ex23_Ex29del. Login to comment
82 Summary of ABCC6/MRP6 mutations identified in German PXE patients Change in Number of Allelic frequency Exona nucleotideb Amino acid Statusc families in blood donorsd Referenceg i-1e c.37-1G>Af altered splicing hm 1 0 / 200 This study 2 c.113G>C p.W38S ht 1 0 / 200 This study i-3 c.346-6G>A altered splicing ht 2 Nd A, B 7 c.754C>T p.L252F ht 1 0 / 200 This study 9 c.1132C>T p.Q378X ht 4 Nd B, C 9 c.1171A>G p.R391G ht 1 Nd B, D 10 c.1244T>C p.V415A ht 1 0 / 200 This study 12 c.1460G>A p.R487Q ht 1 0 / 200 This study 12 c.1491C>A p.N497K ht 1 0 / 200 This study 12 c.1552C>T p.R518X ht 1 Nd B, E i-12 c.1574_1575insG p.L525fsX73 ht 1 0 / 200 This study 16 c.1995delG p.A667fsX20 ht 3 Nd A, F, G 18 c.2252T>A p.M751K ht 3 Nd F, G 18 c.2278C>T p.R760W ht 2 Nd B, F, G Change in Number of Allelic frequency Exona nucleotideb Amino acid Statusc families in blood donorsd Referenceg 18 c.2294G>A p.R765Q ht 2 Nd A, F, G, H 19 c.2552T>C p.L851P ht 1 Nd F i-21 c.2787+1G>T altered splicing ht 7 Nd B, C, F, I, J 22 c.2835_2850del16 p.P946fsX17 ht 1 Nd F 22 c.2855T>G p.F952C ht 1 Nd F 23 c.3145T>G p.S1049A ht 1 0 / 200 This study 23 c.3188T>G p.L1063R ht 1 0 / 200 This study 24 c.3340C>T p.R1114C ht 1 Nd B, K, G, L 24 c.3341G>A p.R1114H ht 1 Nd G, H, L, M 24 c.3389C>T p.T1130M ht 1 Nd B, D, G, H, K, L, M, N 24 c.3413G>A p.R1138Q ht 1 Nd A, B, D, J, K, L, N 24 c.3412C>T p.R1138W ht 1 Nd N 24 c.3421C>T p.R1141X hm, ht 26 Nd B, G, J, K, L, M, N, O, P, Q, R, S i-24 c.3505_3506+2delA GGT altered splicing ht 1 0 / 200 This study i-24 c.3507-3C>T altered splicing ht 2 Nd B 26 c.3715T>C p.Y1239H ht 1 Nd L 26 c.3723G>C p.W1241C ht 1 Nd A, L i-26 c.3736-1G>A altered splicing ht 1 Nd B, L, N 27 c.3775delT p.W1259fsX13 ht 1 Nd B, J, L, O i-27 c.3883-6G>A altered splicing ht 1 Nd B 28 c.3902C>T p.T1301I ht 1 Nd A, G, L 28 c.3932G>A p.G1311E ht 1 Nd L 28 c.3940C>T p.R1314W ht 1 Nd A, G, L 28 c.3941G>A p.R1314Q ht 1 Nd A, B, G, L 29 c.4182delG p.N1394fsX8 ht 2 Nd G, H, L 30 c.4209C>A p.S1403R ht 1 Nd F 31 c.4434delA p.R1479fsX25 hm 1 Nd F 23-29 Ex23_Ex29del p.A999_S1403del ht 5 Nd A, B, D, E, G, H, O, R a The exon that contains the ABCC6 sequence variation. Login to comment
89 Genotypes and phenotypes of the PXE patients analyzed in this study Phenotype Genotypeb No.a Sex, Age Age on diagnosis Organ involvement Mutations 1 M 36 11 E, S, G p.R1141X p.R1141X 2 F 44 39 E, S, G, A p.R1141X Ex23_Ex29del 3 F 41 7 E, S p.R1141X p.R1141X 4 F 46 19 E, S, A p.R1141X p.R1141X 5 F 59 55 E, S, A c.37-1G>A c.37-1G>A 6c F 63 16 E, S, H, V, A Ex23_Ex29del c.4182delG 7 F 24 15 E, S c.4434delA c.4434delA 8 M 60 23 E, S p.Q378X p.R1141X 9 F 79 65 E, S, A c.2787+1G>T p.R1141X 10 F 55 35 E, S, G, H, V, A p.Q378X c.2787+1G>T 11 F 47 14 S c.1995delG c.2787+1G>T 12c F 36 24 E, S c.2787+1G>T c.4182delG 13 F 56 8 E, S p.R1141X c.3507-3C>T 14 M 72 55 E, S, H, V p.R1141X 15 F 69 51 E, S c.1995delG p.R765Q 16 F 19 11 S p.R760W p.R1141X 17c F 59 50 E, S, H, V, A p.R1141X p.G1311E 18c M 54 32 E, S p.R1141X p.Y1239H 19-1 M 63 53 E, H p.L252F p.V415A p.R765Q 19-2 F 58 48 E, S p.L252F p.V415A p.R765Q 20 M 54 44 E, S, V, A c.3775delT c.346-6G>A 21 M 52 43 E, S, A p.R1141X c.3883-6G>A 22-1 M 47 36 E, S, G, H, V p.R518X 22-2 M 45 34 E, S, H p.R518X 23 F 35 22 E, S, A p.W38S 24 F 40 30 E c.346-6G>A 25-1 M 58 46 E, S, A p.R1141X c.3883-6G>A 25-2 M 19 10 S p.R1141X c.3883-6G>A 26-1 F 46 18 E, S, V p.R487Q c.3883-6G>A 27c F 62 30 E, S, A p.Q378X p.R1114H 28 F 59 49 E, A p.R1314Q c.3507-3C>T 29c F 30 10 E, S c.1995delG p.R1114C 30 M 67 52 E p.L1063R p.R1141X 31 F 50 46 E, S, V p.M751K p.R1141X 32 F 27 24 S Ex23_Ex29del 33c F 34 19 E, S Ex23_Ex29del p.T1130M 34 F 33 19 E, S c.2787+1G>T p.W1241C 35 M 47 15 E, S, G, H, V, A Ex23_Ex29del 36 M 72 63 E, S p.S1049A c.3736-1G>A p.S1403R 37 F 34 16 E, S c.2787+1G>T 38 F 42 8 E, S, V p.R1141X p.R1314W 39 F 37 20 E, S p.N497K 40 F 54 33 E, S, V, A p.M751K p.R1141X 41 M 53 49 E, S, G, H, V p.R1141X 42-1 F 52 38 E, S p.R391G p.R1141X 42-2 F 43 28 E, S p.R391G p.R1141X 43 F 64 58 S, A 44-1 F 51 27 E, S, A p.R1141X 44-2 F 18 9 E, S 44-3 F 54 26 E, S, V, A p.R1141X 45-1 F 64 49 E, S, G, V p.R1138Q 45-2 F 62 48 E, S, A p.R1138Q 46 M 56 25 E, S, V p.R1141X p.T1301I 47 F 34 23 E, S p.R760W c.2787+1G>T 48 M 47 24 E, S, V, A c.2835_2850del16 p.F952C p.R1141X 49 F 28 11 E, S, G, V p.M751K p.R1141X 50 F 39 25 E, S, V p.L851P p.R1141X c.3505_3506+2 delAGGT 51 F 61 16 E, S, H, A p.Q378X p.R1141X 52-1 F 40 20 E, S p.R1138W p.R1141X 52-2 F 43 23 E, S p.R1138W p.R1141X 53 M 68 66 E, H, V, G, A c.1574_1575insG p.R1141X F = female, M = male, wt = wild-type, hm = homozygote, ht = heterozygote, cht = compound heterozygote, nd = not determined, MSM = microsatellite marker, E = eyes, S = skin, G = gastrointestinum, H = heart, V = vascular tissue and A = arterial hypertension. Login to comment
97 The other 7 PXE patients were compound heterozygous for the novel DNA variations p.L252F, p.V415A, p.R487Q, p.S1049A, p.L1063R, c.1574_1575insG and c.3505_3506+2delAGGT, as well as for the known PXE-causing mutations p.R765Q, p.R1141X, p.L851P, c.3736-1G>A and p.S1403R (Bergen et al., 2000; Germain et al., 2000; Ringpfeil et al., 2000; Struk et al., 2000; Le Saux et al., 2001; Uitto et al., 2001; Hendig et al., 2005). Login to comment
123 The frequencies of these mutations were similar to those reported in previous European studies, in which the nonsense mutation p.R1141X and the large deletion Ex23_Ex29del were described as frequent ABCC6 mutations in French, Italian and Dutch PXE patients and most of the further ABCC6 alterations were determined as unique mutations (Chassaing et al., 2004; Gheduzzi et al., 2004; Hu et al., 2004). Login to comment
152 For the p.L1063R variant that was found in a compound heterozygous state with the nonsense mutation p.R1141X, segregation with the PXE phenotype within the patient's family was observed (Table 2). Login to comment
162 The mutations p.R1141X, which is found in 2 apparently non-consanguineous parts of the family, p.R487Q and c.3883-6G>A could be located. Login to comment
165 The index patient and her sister were heterozygous for p.R1141X, but no mutation could be detected in the ABCC6 gene of the daughter. Login to comment

PMID: 17251343 [PubMed] Shi Y et al: "Development of a rapid, reliable genetic test for pseudoxanthoma elasticum."

No. Sentence Comment

12 The ABCC6 gene (Online Mendelian Inheritance of Man no. 603234) consists of 31 exons on human chromosome 16p13.1.36 The gene encodes a protein (ABCC6/MRP6) belonging to the ATP-binding cassette membrane transporter family with 1503 amino acid residues, three transmembrane segments consisting of 17 hydrophobic helices, and two conserved nucleotide binding domains (NBD1 and NBD2).7-9 ABCC6 gene mutations have been associated with autosomal recessive and sporadic forms of PXE.5,10 -13 At present, some 150 causative mutations in this gene have been observed in different populations, with most mutations being missense, nonsense, deletion/insertion, or splice site alterations clustered toward the large carboxyl-terminal end of ABCC6/MRP6 in NBD1 and NBD2.5,10 -30 The most frequent mutations in North American, European, and South African populations are c.3421CϾT (p.R1141X) in exon 24 and Alu-mediated deletion of sequences between exon 23 and 29 (ex23_ex29del).14,16,18,19,21,23 Mutations in the ABCC6 gene that cause PXE allow development of genetic tests for accurate clinical diagnosis, differential diagnosis from PXE-like phenotypes (eg, PXE-like papillary dermal elastolysis and fibroelastolytic papulosis, periumbilical perforating PXE, PXE-like presentation of beta-thalassemia, and acquired PXE syndromes), and predictive preclinical diagnosis to allow for possible intervention and for timely genetic counseling. Login to comment
31 The c.3421CϾT (p.R1141X) mutation in exon 24 and the deletion between exon 23 and exon 29 (ex23_ex29del) are those most commonly found in phenotypically positive samples.14,16,18,19,21,23 This published study and unpublished research sponsored by PXE International, in collaboration with Transgenomic, Inc.; Jefferson Medical College, Philadelphia, PA; Ghent University, Ghent, Belgium; and the University of Witwatersrand, Johannesburg, South Africa, determined that mutations in exons 24 and 28 and the deletion of exons 23 to 29 account for ϳ70% of the ABCC6 gene mutations in individuals affected by PXE. Login to comment
76 Because of the one base position difference between mutation c.3412CϾT (p.R1138W) and c.3413GϾA (p.R1138Q) in exon 24 and the 8- and 9-base position differences between the c.3413GϾA and c.3412CϾT mutations and the c.3421CϾT (p.R1141X) mutation in exon 24, the cleavage fragments from these mutations could not be distinguished by agarose gel electrophoresis. Login to comment
82 Nuclease Digestion Fragment Sizes of Common Mutations in PXE Exon 24 and 28 Amino acid change Base change Fragment lengths (bp) p.T1130M c.3389CϾT 251,257/508 p.R1138W c.3412CϾT 274,234/508 p.R1138Q c.3413GϾA 275,233/508 p.R1141X c.3421CϾT 281,227/508 p.R1164X c.3490CϾT 352,156/508 p.G1302R c.3904GϾA 116,289/405 p.R1314Q c.3941GϾA 153,252/405 p.R1339C c.4015CϾT 227,178/405 The total lengths of the amplicons are listed after the slash. Login to comment
107 The two most prevalent mutations were the nonsense mutations c.3421CϾT (p.R1141X) and c.3490CϾT (p.R1164X) in exon 24. c.3421CϾT is the most common mutation found in PXE patients of European origin.14,19,20,23,29 c.3490CϾT is a common mutation in individuals of British descent.16,21 Two DNA samples carried the c.3490CϾT (p.R1339C) missense mutation in one exon 28 allele, and in both cases, IVS28 ϩ 49CϾT was also present. Login to comment
130 Recently, a multiphase strategy was described to screen for PXE mutations in the total coding sequence of the ABCC6 gene.25 PCR-RFLP and long-range PCR were used initially to detect the most common PXE mutations, c.3421CϾT (p.R1141X) and ex23_ex29del, respectively. Login to comment

PMID: 17693525 [PubMed] Zarbock R et al: "Pseudoxanthoma elasticum: genetic variations in antioxidant genes are risk factors for early disease onset."

No. Sentence Comment

53 The most common causative PXE mutations among these patients were the nonsense mutation c.3421CϾT (p.R1141X), the splice site mutation c.2787 ϩ 1GϾT, and the large deletion Ex23_Ex29del. Login to comment
142 b Patients who are (a) homozygous for PXE mutation p.R1141X, c.2787 ϩ 1GϾT, or c.4434delA; and (b) compound heterozygotes for 2 of the PXE mutations p.R1141X, c.2787 ϩ 1GϾT, Ex23_Ex29del, c.4182delG, p.Q378X, c.1995delG, p.E507X, and c.2835_2850del16. Login to comment

PMID: 17724214 [PubMed] Audo I et al: "Pseudoxanthoma elasticum with generalized retinal dysfunction, a common finding?"

No. Sentence Comment

112 On mutation analysis, this patient was homozygous for the p.R1141X nonsense mutation (c.3421C3T) in exon 24 (Fig. 5c). Login to comment

PMID: 18029147 [PubMed] Drera B et al: "Compound heterozygosity for a novel and a recurrent ABCC6 gene mutation in an Italian family with Pseudoxanthoma elasticum."

No. Sentence Comment

11 In particular, the p.R1141X mutation represents about 28% of the mutations detected in the European patients and about 26% in Italian ones [1,6]. Login to comment
22 Sequencing analysis of proband`s genomic DNA, disclosed in exon 24 of ABCC6 gene the c.3397G>T transversion and the c.3421C>T transition, leading to p.G1133C missense and p.R1141X nonsense mutations, respectively (Fig. 2A). Login to comment
28 The specific amplification of both alleles, using a wild type and a mutated forward primer at nucleotide c.3397, and the sequence analysis of the PCR products showed that the p.G1133C substitution was in trans with the p.R1141X nonsense mutation (Fig. 2B). Login to comment
37 The recurrent p.R1141X nonsense mutation has been shown to result in a null allele due to the nonsense-mediated decay of the aberrant mRNA [9]. Login to comment
41 Previously, the p.R1141X mutation was reported to be associated with an increased risk of premature, i.e. under the 50 years, coronary artery disease in patients without PXE signs [10]. Login to comment
43 In the members of our family carrying the p.R1141X, indeed, cardiovascular involvement, i.e. hypertension, premature coronary artery disease, ischemic stroke or mucosal bleeding, was absent. Login to comment
46 In conclusion, we reported a new Italian PXE family showing intra-familiar variability in the onset and in the systems involvement, in which the disease was due to compound heterozygosity for the novel p.G1133C and the recurrent p.R1141X mutations. Login to comment

PMID: 18513494 [PubMed] Garcia-Fernandez MI et al: "Parameters of oxidative stress are present in the circulation of PXE patients."

No. Sentence Comment

74 Table 1 Clinical data of patients Patients' gender/age Clinical scores Mutations Allele 1 Allele 2 M/10 S2E2 c.3413GNA (p.R1138Q) c.3413GNA (p.R1138Q) F/16 S1 c.1171ANG (p.R391G) c.1552CNT (p.R518X) F/18 S3E2V2 c.1484TNA (p.L495H) c.1484TNA (p.L495H) F/21 S2E2 c.2420GNA (p.R807Q) ND F/21 S2E2 c.184TNC (p.Y62H) c.2996_4208del (p.A999_S1403del) F/24 S2E2 c.1799GNA (p.R600H) c.2420GNA (p.R807Q) F/27 S3E2 c.184TNC (p.Y62H) c.2996_4208del (p.A999_S1403del) F/30 S2E2G1 c.2996_4208del (p.A999_S1403del) c.4198GNA (p.E1400K) F/30 S2E3 c.2996_4208del (p.A999_S1403del) c.4198GNA (p.E1400K) M/30 S2E1 c.3421CNT (p.R1141X) c.3735GNA F/32 S2 c.3421CNT (p.R1141X) c.3735GNA F/33 S3E2 c.1987GNA (p.G663S) ND F/33 S3E3 c.1609_1609delG (p.V537fsX26) c.1763_1769del ins56 F/36 S3E2V3 c.3421CNT (p.R1141X) ND F/36 S3E3V2G1 c.3421CNT (p.R1141X) c.3421CNT (p.R1141X) M/39 S1E2V2 c.1552CNT (p.R518X) c.2996_4208del (p.A999_S1403del) M/42 S1E3V2G1 c.1552CNT (p.R518X) c.2996_4208del (p.A999_S1403del) F/43 S3E3 c.1552CNT (p.R518X) c.1552CNT (p.R518X) F/44 S3E2 c.3341GNA (p.R1114H) c.3542GNA (p.G1181D) F/45 S3E3V2C1G1 c.3421CNT (p.R1141X) c.3421CNT (p.R1141X) F/48 S2E2V2 c.1553GNA (p.R518Q) ND M/51 S1E3 c.3662GNA (p.R1221H) ND F/52 S3E3V2 c.3088CNT (p.R1030X) c.3088CNT (p.R1030X) M/54 S1E2G1 c.1799GNA (p.R600H) c.3941GNA (p.R1314Q) F/56 S3E3V2 c.3662GNA (p.R1221H) ND F/60 S2E3V2C1G1 c.951CNA (p.S317R) c.3421CNT (p.R1141X) F/62 S2E3 c.1552CNT (p.R518X) c.3421CNT (p.R1141X) Scores describe the severity of clinical manifestations. Login to comment

PMID: 19054062 [PubMed] Li Q et al: "Pseudoxanthoma elasticum: clinical phenotypes, molecular genetics and putative pathomechanisms."

No. Sentence Comment

4 More recently, missense mutations in the GGCX gene, either in compound heterozygous state or digenic with a recurrent ABCC6 nonsense mutation (p.R1141X), have been identified in patients with PXE-like cutaneous findings and vitamin K-dependent coagulation factor deficiency. Login to comment
64 Two mutations are recurrent and of high frequency: First, the most common recurring mutation, particularly in Caucasian individuals, is p.R1141X in exon 24, with a prevalence of approximately 30% of all PXE mutations. Login to comment
67 Nevertheless, only approximately 10% of all patients in a recent large US and European study (21) were homozygous or compound heterozygous for p.R1141X and del23-29 mutations, indicating that approximately 90% of all individuals in these PXE populations will require further analysis to identify the second mutation or both mutations in the ABCC6 gene causing their disease. Login to comment
173 The analysis revealed the presence of a recurrent mutation, p.R1141X, in the peripheral blood DNA in several family members but not in the proband herself or in her sister (Fig. 5). Login to comment
174 These individuals were heterozygous for the p.R1141X mutation, and no other ABCC6 mutation could be disclosed in this family. Login to comment
178 In contrast, individuals who were heterozygous carriers of the ABCC6 nonsense mutation p.R1141X were also heterozygous carriers of one of the GGCX missense mutations. Login to comment
179 Specifically, the finding of the GGCX missense mutation p.V255M in combination of the ABCC6 nonsense mutation p.R1141X suggests the possibility of digenic inheritance of their cutaneous findings (59). Login to comment
184 Mutation analysis in the nuclear pedigree identified the presence of the p.R1141X nonsense mutation in the ABCC6 gene and two missense mutations, p.V255M and p.S300F, in the GGCX gene, as indicated on the left. Login to comment

PMID: 19116367 [PubMed] Li Q et al: "Co-existent pseudoxanthoma elasticum and vitamin K-dependent coagulation factor deficiency: compound heterozygosity for mutations in the GGCX gene."

No. Sentence Comment

148 Genetic Heterogeneity of PXE The complementary nature of the ABCC6 and GGCX gene defects has been demonstrated by previous phenotypic observations of a family with features of PXE in association with vitamin K-dependent coagulation factor deficiency.20 While some of the members of that family were compound heterozygotes for missense mutations in the GGCX gene, two patients with characteristic PXE-like cutaneous findings were found to be heterozygous for a missense mutation in the GGCX gene (p.V255M) and a recurrent nonsense mutation (p.R1141X) in the ABCC6 gene in trans. Login to comment

PMID: 19726431 [PubMed] De Zaeytijd J et al: "Added value of infrared, red-free and autofluorescence fundus imaging in pseudoxanthoma elasticum."

No. Sentence Comment

78 In 55% of fundi (24/44), the Table 1 Ophthalmological characteristics of patients Case Age, sex Eye BCVA AS Pd`O C(T) ODD NV PDT Anti-VEGF ABCC6 mutations 1 61, F OD 2/10 + + + À + + À p.R1459C/e OS 9/10 + + + À + + À 2 43, F OD 12/10 + + + À À À À p.R1141X/p.R1141X OS 12/10 + + + À À À À 3 35, M OD 11/10 + + + À À À À p.E125K/p.L1025P OS 1/300 + + + À + + + 4 21, M OD 10/10 + + + À À À À p.R1141X/p.R1141X OS 10/10 + + + + À À À 5 11, M OD 10/10 À + + À À À À c.3506+2T/C/e 3506+2T/COS 10/10 À + + À À À À 6 55, F OD 1/20 + + + À + À À p.R1141X/p.R1141X OS 1.5/10 + + + À + À À 7 40, M OD 4/10 + + + À + + À p.R265G/p.R1141X OS 1/10 + + + À + + À 8 22, F OD 10/10 + + + À À À À p.R1141X/p.R1141X OS 10/10 + + + À À À À 9 29, F OD 10/10 + + + À À À À p.G1263R/c.4182delGG OS 10/10 + + + À À À À 10 20, M OD 10/10 + + + + À À À c.3507-3C/A/p.T944I OS 10/10 + + + + À À À 11 37, F OD 10/10 + + + + À À À p.Q154R/e OS 9/10 + + + + À À À 12 66, F OD 1/20 + À À À + À À p.R1141X/p.R1141X OS 1/10 + À À À + À À 13 68, F OD 10/10 + À À À À À À p.R760Q/p.R1141X OS 10/10 + À À À À À À 14 68, M OD 2/10 + À + À + À À p.A1303P/p.L946I OS CF + À + À + À À 15 58, F OD 7/10 + + + À + À + p.R1141X/c.4103delC OS CF + + + À + + À 16 62,M OD 1/20 + + + À + À + p.R1141X/p.Q1237X OS CF + + + À + À À 17 47, F OD 10/10 + À À À À À À c.3506+2T/C/e OS 10/10 + À À À À À À 18 54, F OD 10/10 + + + À + À + p.R1141X/p.A1303P OS 10/10 + + + À À À À 19 30, F OD 10/10 + + + À À À À p.S398R/c.3364delT OS 10/10 + + + À À À À 20 39, F OD 12/10 + + + À À À À p.R1141X/e OS 10/10 + + + À À À À 21 30, F OD 10/10 + + + À À À À p.G666R/c.1868-5T/G OS 10/10 + + + + À À À 22 34, M OD 12/10 + + + À À À À c.3364delT/p.R518X OS 12/10 + + + À À À À anti-VEGF, anti-vascular endothelial growth factor antibodies; AS, angioid streaks; BCVA, best-corrected visual acuity (Snellen); CF, counting fingers; C(T), Comet (tails); F, female; M, male; MD, macular degeneration; NV, neovascularisation; ODD, optic disc drusen; Pd`O, Peau d`Orange; PDT, photodynamic therapy. Login to comment

PMID: 19823106 [PubMed] Finger RP et al: "Fundus autofluorescence in Pseudoxanthoma elasticum."

No. Sentence Comment

31 The analysis of genetic variations in the ABCC6 gene was performed as described elsewhere.18 Briefly, genomic DNA was extracted from ethylenediaminetetraacetic acid (EDTA)-whole blood, and the presence of the frequent ABCC6 gene mutation c.3421CϾT (p.R1141X) and the deletion Ex23-29del were analyzed by real-time polymerase chain reaction assay19 and a polymerase chain reaction method according to Hu et al.20 The exons 1 to 31 of the ABCC6 gene were polymerase chain reactions amplified with ABCC6-specific primers, excluding the amplification of the two ABCC6-pseudogenes ␺1 and ␺2, and analyzed by denaturating high-performance liquid chromatography and direct sequencing as described previously.18 Skin biopsies were taken from areas of visible skin lesions using a punch under local anesthesia. Login to comment
47 of Mutations 1 46 F Positive CA c.3421CϾT (p.R1141X) c.3412CϾT (p.R1138W) 2 2 44 F Positive PA 0 3 39 M NA CA c.3421CϾT (p.R1141X) c.3421CϾT (p.R1141X) 2 4 47 F Positive CA c.3421CϾT (p.R1141X) Ex23-29del 2 5 49 F Positive PA c.3421CϾT (p.R1141X) 1 6 39 M Positive NA 7 57 F NA PA c.3421CϾT (p.R1141X) 1 8 56 F Positive NA 9 51 F Positive PA 0 10 47 M Positive NA 11 39 F NA PA 0 12 58 M NA CA c.3421CϾT (p.R1141X) c.3715TϾC (p.Y1239H) 2 13 24 M Positive CA c.3421CϾT (p.R1141X) Deletion of unknown size 2 14 59 M Positive PA c.3421CϾT (p.R1141X) 1 15 47 F Positive PA c.3421CϾT (p.R1141X) 1 16 41 M Positive CA c.3421CϾT (p.R1141X) IVS27-6 GϾA 2 17 35 F Positive PA 0 18 74 M NA CA c.3421CϾT (p.R1141X) c.3421CϾT (p.R1141X) 2 19 67 F Positive CA c.4182delG Ex23-29del 2 20 70 M Positive CA c.3421CϾT (p.R1141X) c.3188TϾG (p.L1063R) 2 21 46 M Positive CA c.3421CϾT (p.R1141X) c.3421CϾT (p.R1141X) 2 22 61 M Positive NA 23 61 F NA CA c.754CϾT (p.L252F) c.2294GϾA (p.R765Q) 2 24 58 F NA PA 0 25 54 F NA CA c.3421CϾT (p.R1141X) 1 26 50 M Positive NA 27 38 F Positive CA c.113GϾC (p.W38S) 1 28 54 M Positive PA 0 29 52 F Positive NA 30 45 F Positive PA 0 31 45 F NA CA c.3421CϾT (p.R1141X) c.3940CϾT (p.R1314W) 2 32 27 M NA PA c.3421CϾT (p.R1141X) 1 33 59 F Positive NA 34 65 F Positive NA 35 50 M Positive CA c.3421CϾT (p.R1141X) c.2835_2850del16, c.2855TϾG (p.F952C) 3 36 62 F Positive NA 37 48 M Positive NA 38 20 F Positive PA c.3421CϾT (p.R1141X) 1 39 65 F Positive PA c.3421CϾT (p.R1141X) 1 40 13 F Positive CA c.3421CϾT (p.R1141X) c.3421CϾT (p.R1141X) 2 41 65 F Positive PA c.3412CϾT (p.R1138W) 1 42 72 M NA CA c.3421CϾT (p.R1141X) c.1574_1575insG 2 43 39 F NA PA 0 44 67 F NA CA c.3413GϾA (p.R1138Q) 1 45 43 F Positive NA 46 66 F Positive NA *GenBank accession no. Login to comment
50 CA, complete analysis of the coding regions of all exons and adjacent intron sequences, including analysis of the most frequent ABCC6 gene deletion Ex23-29del; PA, partial ABCC6 gene analysis with at least detection of the frequent mutation c.3421CϾT (p.R1141X) and the deletion Ex23-29del, plus potential DHPLC analysis and direct sequencing of selected exons; NA, not available. Login to comment

PMID: 20018285 [PubMed] Pisciotta L et al: "Pseudoxanthoma elasticum and familial hypercholesterolemia: a deleterious combination of cardiovascular risk factors."

No. Sentence Comment

4 Results and conclusions: The patient was a compound heterozygous for two ABCC6 mutations (p.S317R and p.R1141X) and heterozygous for a novel LDLR mutation (p.R574H). Login to comment
28 The proband, indicated by an arrow, was a compound heterozygous for the following ABCC6 gene mutations: (i) c.951 C > A in exon 8 (p.S317R); (ii) c.3421 C > T in exon 24 (p.R1141X). Login to comment
45 Subject (gender) I.1 (F) I.2 (F) I.3 (F) II.1 (F) II.2 (F) II.3 (M) III.1 (F) III.2 (F) III.3 (M) ABCC6 genotype M1/M2 W/M2 W/W W/M1 W/M1 W/M1 W/M1 W/W W/M1 LDLR genotype W/M3 W/W W/W W/M3 W/M3 W/M3 W/W W/M3 W/M3 Age (years) 60 56 34 40 39 36 7 15 8 BMI (kg/m2 ) 24.9 20.5 24.1 20.8 23.4 28.3 17.7 19.9 13.6 TC (mmol/L) 11.50 ± 0.59 7.88 5.53 8.22 7.03 7.19 4.55 5.74 5.71 LDL-C (mmol/L) 9.08 ± 0.54 5.44 3.29 4.96 4.78 5.22 2.75 3.75 3.77 HDL-C (mmol/L) 1.70 ± 0.16 2.01 1.83 2.66 1.89 0.90 1.55 1.52 1.68 TG (mmol/L) 1.93 ± 0.30 0.92 0.87 1.32 0.77 2.31 0.53 1.03 0.57 ApoA-I (mg/dL) 173 ± 10 209 202 226 182 112 192 183 194 ApoB (mg/dL) 246 ± 13 144 97 132 122 135 68 92 95 APOE genotype ␧3␧3 ␧3␧3 ␧3␧3 ␧2␧3 ␧3␧4 ␧2␧3 ␧2␧3 ␧3␧3 ␧3␧4 Values are mean ± SD; all values are before pharmacological treatment; ABCC6 genotype: W = wild type, M1 = c.951 C > A (p.S317R), M2 = c.3421 C > T (p.R1141X); LDLR genotype: W = wild type, M3 = c.1721 G > A (p.R574H). Login to comment
50 Sequence of ABCC6 gene The proband was compound heterozygous for mutations in ABCC6 gene: (i) a C > A transversion in exon 8 (c.951 C > A), which results in arginine for serine conversion at position 317 (p.S317R); (ii) a C > T transition in exon 24 (c.3421 C > T), which converts arginine codon at position 1141 into a termination codon (p.R1141X). Login to comment
51 One of the proband`s sisters (subject I.2) was a carrier of the p.R1141X mutation. Login to comment
64 Screening for the ABCC6 mutations Both mutations, p.S317R and p.R1141X, were screened in 106 healthy controls. Login to comment
66 The p.R1141X was also screened in 173 patients with premature CAD (before 55 years in males and 65 years in females) (Supplementary Table 1) Three carriers (two males and one female) were found among subjects of this group (1.7%). Login to comment
84 In this context it is noteworthy the observation that the frequency of the p.R1141X mutation of ABCC6 gene (the most common mutation in PXE) was found to be increased (3.3% vs. 0.8%) in a large group of patients with premature coronary heart disease [8]. Login to comment

PMID: 20032990 [PubMed] Uitto J et al: "Pseudoxanthoma elasticum: molecular genetics and putative pathomechanisms."

No. Sentence Comment

71 Two recurrent mutations of high frequency have been identified: p.R1141X in exon 24 is the most common, particularly in Caucasian individuals, with a prevalence of approximately 30% of all pathologic PXE mutations (Pfendner et al., 2007). Login to comment
118 In a particularly illustrative family, individuals were shown to be heterozygous for a nonsense mutation (p.R1141X) in ABCC6 and a missense mutation (p.V255M) in GGCX. Login to comment

PMID: 21671388 [PubMed] Uitto J et al: "Pseudoxanthoma elasticum: progress in diagnostics and research towards treatment : Summary of the 2010 PXE International Research Meeting."

No. Sentence Comment

25 There are recent suggestions, however, that certain mutations in ABCC6 may bestatistically associatedwithinvolvementofspecifictargetorgans, such as the p.R1268Q mutation being associated with early onset of angioidstreaks[Satoetal.,2009;Lietal.,2011a],andthestopcodon mutation p.R1141X possibly predisposing the individuals to car- diovascularinvolvementindependentofhyperlipidemiainpatients with PXE [K€obl€os et al., 2010; Pisciotta et al., 2010]. Login to comment

PMID: 22763786 [PubMed] Ratajewski M et al: "ABCC6 expression is regulated by CCAAT/enhancer-binding protein activating a primate-specific sequence located in the first intron of the gene."

No. Sentence Comment

20 Stop codon mutation p.R1141X represents 25% of all observed mutations. Login to comment

PMID: 23248644 [PubMed] Le Saux O et al: "The molecular and physiological roles of ABCC6: more than meets the eye."

No. Sentence Comment

167 However, this is not without controversy as a much larger study based on 66,831 individuals has found no risk for ischemic heart diseases associated with the ABCC6 p.R1141X mutation (Hornstrup et al., 2011). Login to comment
168 Stroke is also a vascular-related condition frequently reported in PXE patients (Aessopos et al., 1997; van den Berg et al., 2000) but it could well be that strokes etiology in certain PXE individuals might not be related to ABCC6 deficiency as Hornstrup et al. could not statistically link cerebrovascular diseases with the most frequent ABCC6 mutation (p.R1141X). Login to comment

PMID: 23408347 [PubMed] Leftheriotis G et al: "The vascular phenotype in Pseudoxanthoma elasticum and related disorders: contribution of a genetic disease to the understanding of vascular calcification."

No. Sentence Comment

118 In the coronary arterial bed, the association with a heterozygous R1141X mutation in ABCC6 and ischemic vascular events including stroke, was not demonstrated in the general population (n = 66831 participants; Hornstrup et al., 2011), although a strong association was reported only with coronary artery disease (Koblos et al., 2010). Login to comment

PMID: 23674961 [PubMed] Mizutani Y et al: "ABCC6 Mutation in Patients with Angioid Streaks."

No. Sentence Comment

101 However, some previous studies reported that R1141X mutation in exon 24 was the most frequent mutation in PXE (20, 21). Login to comment

PMID: 23702584 [PubMed] Zhou Y et al: "Premature termination codon read-through in the ABCC6 gene: potential treatment for pseudoxanthoma elasticum."

No. Sentence Comment

4 Considering the redundancy of the genetic code, it was postulated that in case of the most common recurrent nonsense mutation, p.R1141X, the read-through may result in substitution of the arginine 1,141 by glycine, tryptophan, or cysteine. Login to comment
20 Received 1 March 2013; revised 17 April 2013; accepted 27 April 2013; accepted article preview online 23 May 2013; published online 27 June 2013 Abbreviations: mRNA, messenger RNA; PXE, pseudoxanthoma elasticum 2672 Journal of Investigative Dermatology (2013), Volume 133 & 2013 The Society for Investigative Dermatology recurrent nonsense mutation is p.R1141X, which accounts for B30% of all pathogenic PXE mutations in Caucasian patient populations. Login to comment
26 In this study, we focused on seven of them, including the most common stop codon mutation, p.R1141X, in which the arginine at position 1,141 (codon CGA) has been replaced by a stop codon (TGA) (Table 1). Login to comment
38 Different pseudoxanthoma elasticum (PXE)- associated nonsense mutations tested for PTC124 read-through Mutation Nucleotide sequence1 Location (exon) Mutation frequency (%)2 p.R1141X TGA-A 24 54 p.R1164X TGA-C 24 10 p.R518X TGA-G 12 1.2 p.R1398X TGA-G 29 1.2 p.Q378X TAG-A 9 o1 p.Q1143X TAG-G 24 o1 p.R1275X TGA-C 27 o1 1 The sequence depicts the stop codon (bold) followed by the nucleotide shown. Login to comment
42 An expression vector (p.CMV6-Entry) containing full-length wild-type human ABCC6 cDNA (a) or a corresponding mutant cDNA harboring p.R1141X premature termination codon containing a 30 -end sequence that encodes a DDK reporter peptide (b, c) or p.R1275X (d) was transfected into HEK293 cells in culture without (a, b) or with PTC124 (10mg ml 1 for 72hours) (c, d). Login to comment
50 In case of the p.R1141X mutation, considering the codon redundancy and possible combinations of the corrected mutations from the stop codon (TGA) to an amino acid, in addition to arginine (CGA), this position could be occupied either by cysteine (TGC) or tryptophan (TGG) or glycine (GGA). Login to comment
71 In contrast, injection of human ABCC6 mRNA harboring the p.R1141X stop codon mutation failed to reverse the phenotype (Figure 5d and Table 2), suggesting that this mRNA rescue system can be used to check the pathogenicity of mutant human ABCC6 proteins, including those harboring the missense amino acids as a result of PTC124 read-through. Login to comment
87 However, injection of human ABCC6 mRNA, which harbors the p.R1141X mutation, does not result in phenotypic rescue (d). Login to comment
90 of embryos injected Lethality (%)2 Mo - 107 71.0 Scmo - 108 12.0 Mo&#fe; WT Arg 96 9.4 Mo&#fe; TGA STOP 102 85.3 Mo&#fe; TGG Trp 94 26.6 Mo&#fe; TGC Cys 134 7.5 Mo&#fe; GGA Gly 125 16.0 1 Zebrafish embryos were injected at day 0 with an abcc6a morpholino (Mo) alone or with human ABCC6 mRNA, either wild type (WT) harboring arginine at position 1,141, corresponding to the p.R1141X stop codon mutation (TGA), or containing a missense substitution of tryptophan (TGG), cysteine (TGC), or glycine (GGA) instead of arginine at position 1,141. Login to comment
93 ABCC6 with p.R1141X mutations in both alleles on the Abcc6 / background. Login to comment
95 It is conceivable that the presence of such an amino acid carried by a near-cognate transfer RNA (instead of the parent wild-type arginine in case of p.R1141X) could be pathogenic, essentially representing a missense mutation. Login to comment
132 Capped full-length human ABCC6 mRNA corresponding to wild-type, R1141X, or putative read-through substitutions of arginine1141 by cysteine, tryptophan, or glycine was transcribed from an expression vector pCMV-Tag4B using the T3 mMessage mMachine kit (Ambion, Austin, TX). Login to comment

PMID: 23802012 [PubMed] Hendig D et al: "New insights into the pathogenesis of pseudoxanthoma elasticum and related soft tissue calcification disorders by identifying genetic interactions and modifiers."

No. Sentence Comment

22 The most frequent mutation found in PXE patients is a nonsense mutation in exon 24, p.R1141X (c.3421C>T, rs72653706), which is found in approximately 25% of the European patient population. Login to comment
40 Mother and maternal aunt were identified as compound heterozygous carriers of the recurrent ABCC6 nonsense mutation p.R1141X and a missense mutation in GGCX (p.S300F). Login to comment
118 Few studies investigated the correlation of ABCC6 mutations with cardiovascular disease and identified the frequent mutation p.R1141X as a strong genetic risk factor for CAD (Trip et al., 2002; Wegman et al., 2005; K&#f6;bl&#f6;s et al., 2010). Login to comment

PMID: 23807484 [PubMed] Guo H et al: "Atorvastatin counteracts aberrant soft tissue mineralization in a mouse model of pseudoxanthoma elasticum (Abcc6(-)/(-))."

No. Sentence Comment

1 Previous studies have suggested that carriers of the ABCC6 mutations, particularly of p.R1141X, are at increased risk for coronary artery disease. Login to comment
23 However, it has been suggested that heterozygous carrier status of loss-of-function mutations in the ABCC6 gene, particularly that of p.R1141X, the most common mutation in the Caucasian populations, is associated with a strong increase in the prevalence of coronary artery disease [13, 14]. Login to comment

PMID: 23968982 [PubMed] Campens L et al: "Characterization of cardiovascular involvement in pseudoxanthoma elasticum families."

No. Sentence Comment

86 Patients with PXE generally have a normal life span but are prone to vascular disease, such as CAD, PAD, and cerebrovascular disease.3 Conversely, a large population-based study showed an association between premature CAD and a frequent mutation in the ABCC6 gene (R1141X).12 As such, PXE can serve as a genetic model for the study of the pathophysiology of common cardiovascular diseases. Login to comment

PMID: 24008425 [PubMed] Li Q et al: "Mutations in the ABCC6 gene as a cause of generalized arterial calcification of infancy: genotypic overlap with pseudoxanthoma elasticum."

No. Sentence Comment

36 Family D 1 2 1 Family E c.3692insTT +/- 1 2 1 2 3 Family F I II g.del23-29 +/- p.R760W +/- 1 2 1 2 3 4 1 2 1 2 1 2 1 Family A Family B Family C I II p.R1314W +/- p.R1314W +/- c.2787+1G>T c.3736-1G>A +/- p.R391G +/- p.R391G +/- p.R1141X +/- c.346-6G>A +/- +/+ 1 2 3 4 p.R1141X +/+ +/- c.346-6G>A +/- 1 2 -/- -/- +/- +/+ +/+ +/+ +/- +/+ Figure 1. Login to comment
43 The proband in Family D (patient 5) had compound heterozygous mutations c.346-6G4A and p.R1141X in intron 3 and exon 24 of ABCC6. Login to comment

PMID: 24352041 [PubMed] Pomozi V et al: "Analysis of pseudoxanthoma elasticum-causing missense mutants of ABCC6 in vivo; pharmacological correction of the mislocalized proteins."

No. Sentence Comment

39 In addition to 10 missense mutants, R1141X was also used as a negative control in certain experiments. Login to comment
50 The nonsense R1141X mutant was not expressed in Sf9 cells. Login to comment
51 Subcellular localization in vitro Each mutant (with the exception of R1141X) was individually expressed in MDCKII cells, which were then grown either on plastic wells as nonpolarized cells or on Transwell filters, which ensures development of monolayers of polarized cells. Login to comment
67 The R1141X mutant was not expressed in the mouse liver. Login to comment
72 Next, the injection of the nonsense R1141X mRNA showed that this mutant was ineffective in rescuing the morpholino-mediated phenotype (4.8%). Login to comment
133 (d) Animals injected with morpholino and with ABCC6 R1141X mRNA. Login to comment
150 Summary of the characterization and rescue of disease-causing ABCC6 mutants Localization in mouse liver Localization in MDCKII cell line Nonpolarized Polarized ABCC6 variant Sf9 transport activity Without treatment After 4-PBA treatment Without treatment After 4-PBA treatment Without treatment After 4-PBA treatment Zebrafish &#fe; mRNA rescue (%) Wild type Active PM1 PM PM PM PM PM 90.6 R1114P Active IC4PM PM (rescue) ICoPM PM (rescue) PM PM 0.0 S1121W Active IC4PM PM (rescue) PM PM PM PM 7.9 R1138Q Active IC4PM IC4PM (no effect) IC PM (rescue) PM PM 1.8 V1298F o20% PM ND PM PM PM ND 32.0 T1301I Active IC4PM IC4PM (no effect) IC4PM PM (rescue) PM PM 5.1 R1314W1 Active IC4PM PM (rescue) IC PM (rescue) IC4PM PM (rescue) 0.0 G1321S o20% IC ND IC4PM IC4PM (no effect) IC IC (no effect) 0.0 R1339C Not stable IC IC (no effect) IC IC (no effect) IC IC (no effect) 0.0 Q1347H Active IC4PM PM (rescue) IC4PM PM (rescue) IC &#bc; PM IC&#bc; PM (no effect) 0.8 R1459C Active PM ND IC &#bc; PM PM (rescue) ICoPM ICoPM (no effect) 0.0 delABCC6 o20% IC IC IC IC IC IC ND R1141X Stop ND ND ND ND ND ND 4.8 Abbreviations: IC, intracellular; ND, not determined; PM, plasma membrane. Login to comment

PMID: 24840500 [PubMed] Xue P et al: "Regulation of ABCC6 trafficking and stability by a conserved C-terminal PDZ-like sequence."

No. Sentence Comment

430 Wegman JJ, Hu X, Tan H, Bergen AA, Trip MD, et al. (2005) Patients with premature coronary artery disease who carry the ABCC6 R1141X mutation have no Pseudoxanthoma Elasticum phenotype. Login to comment

PMID: 25064003 [PubMed] Kuzaj P et al: "ABCC6- a new player in cellular cholesterol and lipoprotein metabolism?"

No. Sentence Comment

228 Pisciotta et al. examined a hypercholesterolemic PXE patient, who was compound-heterozygous for two ABCC6 mutations (p.S317R and p.R1141X) and for further mutations in candidate genes causing autosomal co-dominant hypercholesterolemia [54]. Login to comment

PMID: 25264593 [PubMed] Hosen MJ et al: "Efficiency of exome sequencing for the molecular diagnosis of pseudoxanthoma elasticum."

No. Sentence Comment

89 List of mutations found by WES and SS Gene Nucleotide change Protein change Patient ID Hom/Het WES SS Known/PUR Reference ABCC6 c.C118T p.(P40S) P10 Het O O PUR ABCC6 c.998 &#fe; 2 998 &#fe; 3del TG P8 Het O O PUR ABCC6 c.T1484A p.(L495H) P7 Het O O Known Miksch et al., 2005 ABCC6 c.G1553A p.(R518Q) P11 Hom O O Known Uitto et al., 2001 ABCC6 c.G1553A p.(R518Q) P12, P13, P14 Het O O Known Uitto et al., 2001 ABCC6 c.G2263A p.(G755R) P11 Het O O Known Pfendner et al., 2007 ABCC6 c.G2294A p.(R765Q) P3 Het O O Known Le Saux et al., 2001 ABCC6 del2860_2865 P12, P13,14 Het O O PUR ABCC6 c.T2911C p.(W971R) P11 Het O O PUR ABCC6 Ex23_24del P2 Hom O O Known Ringpfeil et al., 2001 ABCC6 c.T3032C p.(L1011P) P9 Hom O O PUR ABCC6 c.C3190T p.(A1064T) P7 Het O O Known Miksch et al., 2005 ABCC6 c.G3413A p.(R1138Q) P11 Het O O Known Le Saux O, 2011 ABCC6 c.C3421T p.(R1141X) P4 Hom O O Known Bergen et al., 2000 ABCC6 c.C3421T p.(R1141X) P52 , P8, P162 Het O O Known Bergen et al., 2000 ABCC6 c.C3490T p.(R1164X) P6, P15 Hom O O Known Struk et al., 2000 ABCC6 c.G4198A p.(E1400K) P10 Het O O Known Chassaing et al., 2004 ABCC6 c.C4216A p.(Q1406K) P3 Het O O PUR GGCX c.C1321T p.(R441C) P7 Het O O PUR Het, heterozygous; Hom, homozygous; PUR, previously unreported; SS, Sanger sequencing; WES, whole-exome sequencing. Login to comment
99 In some of these, the p.(R1141X) mutation has been correlated with the presence of coronary artery disease (Trip et al., 2002; Sherer et al., 2001). Login to comment
100 In our cohort, two heterozygous patients, P5 and P16, carry the p.(R1141X) mutation (Table 2). Login to comment

PMID: 25265166 [PubMed] Kuzaj P et al: "Large-scaled metabolic profiling of human dermal fibroblasts derived from pseudoxanthoma elasticum patients and healthy controls."

No. Sentence Comment

19 The prevalence of the autosomal recessive disease PXE is estimated to be between 1:25.000 and 1:100.000 [4], and to date up to 350 ABCC6 mutations were described [7] with p.R1141X (20-30%) and c.EX23_EX29del (515%) being the most frequent in European PXE patients [8]. Login to comment
159 Interestingly, fibroblasts from PXE patient 2 showing the lowest protein content, were found to carry two heterozygous ABCC6 mutations c.3421C.T (p.R1141X) and c.2787+1G.T. Login to comment
160 Furthermore, PXE patient 5 with 69% protein level detected, exhibit a genetic variation within the promotor region (c.-90ins14) in addition to the frequently observed c.3421C.T (p.R1141X) mutation. Login to comment
342 Hu X, Peek R, Plomp A, ten Brink J, Scheffer G, et al. (2003) Analysis of the frequent R1141X mutation in the ABCC6 gene in pseudoxanthoma elasticum. Login to comment

PMID: 25367056 [PubMed] Giovannoni I et al: "Heart transplant and 2-year follow up in a child with generalized arterial calcification of infancy."

No. Sentence Comment

56 A compound heterozygosity was identified in ABCC6: the mutations were located at nucleotide position c.1132C>T (p.Q378X) and c.3421C>T (p.R1141X). Login to comment
58 Segregation analysis showed a compound heterozygous mutations with c.1132C>T (p.Q378X) and del_24-27 in the mother and a double heterozygous mutations c.1132C>T (p.Q378X) and c.3421C>T (p.R1141X) in the father. Login to comment
85 Fig. 2 Pedigree and haplotype analysis with markers from the ABCC6 regions: a double mutation on the same allele in cis (p.Q378X, p.R1141X) was found in the father and a mutation on the other allele in trans (p.Q378X, del_24-27) was found in the mother, affected by PXE (asterisk); the patient showed a compound heterozygous mutations of p.Q378X, p.R1141X, and del_24-27 Conclusions In this child with GACI and end-stage myocardial ischemia, the transplant solved the heart failure as observed throughout the 2-year follow-up and no new calcifications have been observed at the cardiac level (no coronary deposits). Login to comment

PMID: 25383264 [PubMed] Uitto J et al: "PSEUDOXANTHOMA ELASTICUM: DIAGNOSTIC FEATURES, CLASSIFICATION, AND TREATMENT OPTIONS."

No. Sentence Comment

49 In particular, heterozygous carriers of the loss-of-function mutation p.R1141X, the most common mutation in the Caucasion populations, is associated with a strong increase in the prevalence of coronary artery disease [17-19] Uitto et al. Page 3 3. Login to comment
149 Approximately 40% of all ABCC6 gene mutations in patients with PXE consist of PTCs, including p.R1141X, which accounts ~25% of all mutations in PXE [8]. Login to comment
231 Frequent mutation in the ABCC6 gene (R1141X) is associated with a strong increase in the prevalence of coronary artery disease. Login to comment
235 K&#f6;bl&#f6;s G, Andrikovics H, Proh&#e1;szka Z, et al. The R1141X loss-of-function mutation of the ABCC6 gene is a strong genetic risk factor for coronary artery disease. Login to comment

PMID: 25640304 [PubMed] Harrington C et al: "The prevalence of pseudoxanthoma elasticum-like connective tissue changes in an oral biopsy service and review of the literature."

No. Sentence Comment

71 Mutation analysis of the ABCC6 gene in these families clarified and confirmed an autosomal recessive mode of inheritance.4 Two-generation involvement is explained by pseudodominance.1,4,5,16 Consanguinity is strongly associated with PXE but may be difficult to confirm either because of the reluctance of current family members to discuss or disclose such a possibility or because a confident determination is simply not possible with past generations.9 ABCC6, the affected gene in PXE, was discovered in 2000,16,20-22 which led to the conclusion that PXE is a primary metabolic disorder with secondary connective tissue manifestations.23-25 Over 300 mutations of the ABCC6 gene have been identified,19 with R1141X being the most common.14,33,40 ABCC6, also known as "multidrug resistanceeassociated protein 6" (MRP6), is a member of the C-family of adenosine triphosphate (ATP)e binding cassette proteins located on chromosome 16.20,41 ABCC6 is found mainly in the liver but is also found in the kidneys and serves as a transporter of Table I. Prevalence of positive findings by decade, gender and overall (N &#bc; 500) Gender Decade First Second Third Fourth Fifth Sixth Seventh Eighth Ninth All Female Estimate 0.0 0.0 0.0 8.8 12.0 12.5 16.2 27.6 20.0 10.1 (LCB.95) 0.0 0.0 0.0 1.9 2.6 4.7 6.2 12.7 2.5 6.8 (UCB.95) 0.0 0.0 0.0 23.7 31.2 25.3 32.0 47.2 55.6 14.3 Male Estimate 0.0 0.0 3.5 11.8 8.0 6.5 28.1 8.3 66.7 9.4 (LCB.95) 0.0 0.0 0.1 3.3 0.1 0.7 13.8 0.2 9.4 5.9 (UCB.95) 0.0 0.0 17.8 27.5 26.0 21.4 46.8 38.5 99.2 14.0 All Estimate 0.0 0.0 1.9 10.3 10.0 10.1 21.7 22.0 30.8 9.8 (LCB.95) 0.0 0.0 0.1 4.4 3.3 4.5 12.7 10.6 9.1 7.3 (UCB.95) 0.0 0.0 9.9 20.0 21.8 19.0 33.3 37.6 61.4 12.8 LCB, lower confidence bound; UCB, upper confidence bound. Login to comment

PMID: 25735631 [PubMed] Charbel Issa P et al: "[Pseudodominant inheritance of pseudoxanthoma elasticum]."

No. Sentence Comment

78 Hornstrup LS,Tybjaerg-Hansen A, Haase CL et al (2011) Heterozygosity for R1141X in ABCC6 and risk of ischemic vascular disease. Login to comment
80 K&#f6;bl&#f6;s G, Andrikovics H, Prohaszka Z et al (2010) The R1141X loss-of-function mutation of the ABCC6 gene is a strong genetic risk factor for coronary artery disease. Login to comment
92 Trip MD, SmuldersYM,Wegman JJ et al (2002) Frequent mutation in the ABCC6 gene (R1141X) is associated with a strong increase in the prevalence of coronary artery disease. Login to comment