ABCC6 p.Arg1314Gln
| ClinVar: |
c.3940C>T
,
p.Arg1314Trp
D
, Pathogenic
|
| LOVD-ABCC6: |
p.Arg1314Gln
D
p.Arg1314Trp D |
| Predicted by SNAP2: | A: D (95%), C: D (95%), D: D (95%), E: D (95%), F: D (95%), G: D (95%), H: D (95%), I: D (95%), K: D (95%), L: D (95%), M: D (95%), N: D (95%), P: D (95%), Q: N (61%), S: D (95%), T: D (95%), V: D (95%), W: D (71%), Y: D (95%), |
| Predicted by PROVEAN: | A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: D, K: D, L: D, M: D, N: D, P: D, Q: D, S: D, T: D, V: D, W: D, Y: D, |
[switch to compact view]
Comments [show]
None has been submitted yet.
[hide] A spectrum of ABCC6 mutations is responsible for p... Am J Hum Genet. 2001 Oct;69(4):749-64. Epub 2001 Aug 31. Le Saux O, Beck K, Sachsinger C, Silvestri C, Treiber C, Goring HH, Johnson EW, De Paepe A, Pope FM, Pasquali-Ronchetti I, Bercovitch L, Marais AS, Viljoen DL, Terry SF, Boyd CD
A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum.
Am J Hum Genet. 2001 Oct;69(4):749-64. Epub 2001 Aug 31., [PMID:11536079]
Abstract [show]
To better understand the pathogenetics of pseudoxanthoma elasticum (PXE), we performed a mutational analysis of ATP-binding cassette subfamily C member 6 (ABCC6) in 122 unrelated patients with PXE, the largest cohort of patients yet studied. Thirty-six mutations were characterized, and, among these, 28 were novel variants (for a total of 43 PXE mutations known to date). Twenty-one alleles were missense variants, six were small insertions or deletions, five were nonsense, two were alleles likely to result in aberrant mRNA splicing, and two were large deletions involving ABCC6. Although most mutations appeared to be unique variants, two disease-causing alleles occurred frequently in apparently unrelated individuals. R1141X was found in our patient cohort at a frequency of 18.8% and was preponderant in European patients. 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. Putative disease-causing mutations were identified in approximately 64% of the 244 chromosomes studied, and 85.2% of the 122 patients were found to have at least one disease-causing allele. Our results suggest that a fraction of the undetected mutant alleles could be either genomic rearrangements or mutations occurring in noncoding regions of the ABCC6 gene. The distribution pattern of ABCC6 mutations revealed a cluster of disease-causing variants within exons encoding a large C-terminal cytoplasmic loop and in the C-terminal nucleotide-binding domain (NBD2). We discuss the potential structural and functional significance of this mutation pattern within the context of the complex relationship between the PXE phenotype and the function of ABCC6.
Comments [show]
None has been submitted yet.
No. Sentence 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.
X
ABCC6 p.Arg1314Gln 11536079:85:1804
status: NEW94 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 ?
X
ABCC6 p.Arg1314Gln 11536079:94:1128
status: NEW[hide] ABCC6/MRP6 mutations: further insight into the mol... Eur J Hum Genet. 2003 Mar;11(3):215-24. Hu X, Plomp A, Wijnholds J, Ten Brink J, van Soest S, van den Born LI, Leys A, Peek R, de Jong PT, Bergen AA
ABCC6/MRP6 mutations: further insight into the molecular pathology of pseudoxanthoma elasticum.
Eur J Hum Genet. 2003 Mar;11(3):215-24., [PMID:12673275]
Abstract [show]
Pseudoxanthoma elasticum (PXE) is a hereditary disease characterized by progressive dystrophic mineralization of the elastic fibres. PXE patients frequently present with skin lesions and visual acuity loss. Recently, we and others showed that PXE is caused by mutations in the ABCC6/MRP6 gene. However, the molecular pathology of PXE is complicated by yet unknown factors causing the variable clinical expression of the disease. In addition, the presence of ABCC6/MRP6 pseudogenes and multiple ABCC6/MRP6-associated deletions complicate interpretation of molecular genetic studies. In this study, we present the mutation spectrum of ABCC6/MRP6 in 59 PXE patients from the Netherlands. We detected 17 different mutations in 65 alleles. The majority of mutations occurred in the NBF1 (nucleotide binding fold) domain, in the eighth cytoplasmatic loop between the 15th and 16th transmembrane regions, and in NBF2 of the predicted ABCC6/MRP6 protein. The R1141X mutation was by far the most common mutation identified in 19 (32.2%) patients. The second most frequent mutation, an intragenic deletion from exon 23 to exon 29 in ABCC6/MRP6, was detected in 11 (18.6%) of the patients. Our data include 11 novel ABCC6/MRP6 mutations, as well as additional segregation data relevant to the molecular pathology of PXE in a limited number of patients and families. The consequences of our data for the molecular pathology of PXE are discussed.
Comments [show]
None has been submitted yet.
No. Sentence 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.
X
ABCC6 p.Arg1314Gln 12673275:38:1117
status: NEW[hide] Pseudoxanthoma elasticum: a clinical, histopatholo... Surv Ophthalmol. 2003 Jul-Aug;48(4):424-38. Hu X, Plomp AS, van Soest S, Wijnholds J, de Jong PT, Bergen AA
Pseudoxanthoma elasticum: a clinical, histopathological, and molecular update.
Surv Ophthalmol. 2003 Jul-Aug;48(4):424-38., [PMID:12850230]
Abstract [show]
Pseudoxanthoma elasticum is an autosomally inherited disorder that is associated with the accumulation of mineralized and fragmented elastic fibers in the skin, Bruch's membrane in the retina, and vessel walls. The ophthalmic and dermatologic expression of pseudoxanthoma elasticum and its vascular complications are heterogeneous, with considerable variation in phenotype, progression, and mode of inheritance. Using linkage analysis and mutation detection techniques, mutations in the ABCC6 gene were recently implicated in the etiology of pseudoxanthoma elasticum. ABCC6 encodes the sixth member of the ATP-binding cassette transporter and multidrug resistance protein family (MRP6). In humans, this transmembrane protein is highly expressed in the liver and kidney. Lower expression was found in tissues affected by pseudoxanthoma elasticum, including skin, retina, and vessel walls. So far, the substrates transported by the ABCC6 protein and its physiological role in the etiology of pseudoxanthoma elasticum are not known. A functional transport study of rat MRP6 suggests that small peptides such as the endothelin receptor antagonist BQ123 are transported by MRP6. Similar molecules transported by ABCC6 in humans may be essential for extracellular matrix deposition or turnover of connective tissue at specific sites in the body. One of these sites is Bruch's membrane. This review is an update on etiology of pseudoxanthoma elasticum, including its clinical and genetic features, pathogenesis, and biomolecular basis.
Comments [show]
None has been submitted yet.
No. Sentence 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.
X
ABCC6 p.Arg1314Gln 12850230:193:1053
status: NEW[hide] Pseudoxanthoma elasticum: a clinical, pathophysiol... J Med Genet. 2005 Dec;42(12):881-92. Epub 2005 May 13. Chassaing N, Martin L, Calvas P, Le Bert M, Hovnanian A
Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations.
J Med Genet. 2005 Dec;42(12):881-92. Epub 2005 May 13., [PMID:15894595]
Abstract [show]
Pseudoxanthoma elasticum (PXE) is an inherited systemic disease of connective tissue primarily affecting the skin, retina, and cardiovascular system. It is characterised pathologically by elastic fibre mineralisation and fragmentation (so called "elastorrhexia"), and clinically by high heterogeneity in age of onset and the extent and severity of organ system involvement. PXE was recently associated with mutations in the ABCC6 (ATP binding cassette subtype C number 6) gene. At least one ABCC6 mutation is found in about 80% of patients. These mutations are identifiable in most of the 31 ABCC6 exons and consist of missense, nonsense, frameshift mutations, or large deletions. No correlation between the nature or location of the mutations and phenotype severity has yet been established. Recent findings support exclusive recessive inheritance. The proposed prevalence of PXE is 1/25,000, but this is probably an underestimate. ABCC6 encodes the protein ABCC6 (also known as MRP6), a member of the large ATP dependent transmembrane transporter family that is expressed predominantly in the liver and kidneys, and only to a lesser extent in tissues affected by PXE. The physiological substrates of ABCC6 remain to be determined, but the current hypothesis is that PXE should be considered to be a metabolic disease with undetermined circulating molecules interacting with the synthesis, turnover, or maintenance of elastic fibres.
Comments [show]
None has been submitted yet.
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.
X
ABCC6 p.Arg1314Gln 15894595:378:730
status: NEW379 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.
X
ABCC6 p.Arg1314Gln 15894595:379:1412
status: NEW[hide] Analysis of sequence variations in the ABCC6 gene ... J Vasc Res. 2005 Sep-Oct;42(5):424-32. Epub 2005 Aug 26. Schulz V, Hendig D, Schillinger M, Exner M, Domanovits H, Raith M, Szliska C, Kleesiek K, Gotting C
Analysis of sequence variations in the ABCC6 gene among patients with abdominal aortic aneurysm and pseudoxanthoma elasticum.
J Vasc Res. 2005 Sep-Oct;42(5):424-32. Epub 2005 Aug 26., [PMID:16127278]
Abstract [show]
Abdominal aortic aneurysm (AAA) is characterized by dilatation of arterial walls, which is accompanied by degradation of elastin and collagen molecules. Biochemical and environmental factors are known to be relevant for AAA development, and familial predisposition is well recognized. A connective tissue disorder that is also associated with fragmentation of elastic fibers is Pseudoxanthoma elasticum (PXE). PXE is caused by mutations in the ABCC6 gene and mainly affects dermal, ocular and all vascular tissues. To investigate whether variations in ABCC6 are found in AAA patients and to determine mutations in PXE patients, we analyzed seven selected ABCC6 exons of 133 AAA and 54 PXE patients subjected to mutational analysis. In our cohort of AAA patients, we found five ABCC6 alterations, which result in missense or silent amino acid variants. The allelic frequencies of these sequence variations were not significantly different between AAA patients and healthy controls. Therefore, we suggest that alterations in ABCC6 are not a genetic risk factor for AAA. Mutational screening of the PXE patients revealed 19 different ABCC6 variations, including two novel PXE-causing mutations. These results expand the ABCC6 mutation database in PXE.
Comments [show]
This is erroneously identified as a reported sequence variant. In the cited article E18L is the name of a PCR primer.
aranyi on 2012-05-05 13:15:49
aranyi on 2012-05-05 13:15:49
No. Sentence Comment
109 In addition, we detected a silent variation (p.V725V) and 14 missense mutations (p.R724K, p.I742V, p.M751K, p.R760W, p.R765Q, p.R1114C, p.R1114H, p.T1130M, p.R1138Q, p.T1301I, p.G1311E, p.R1314Q, p.R1314W and p.S1403R) in their heterozygous, compound heterozygous and homozygous forms in 17 PXE patients.
X
ABCC6 p.Arg1314Gln 16127278:109:188
status: NEW116 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.
X
ABCC6 p.Arg1314Gln 16127278:116:953
status: NEW[hide] Mutation detection in the ABCC6 gene and genotype-... J Med Genet. 2007 Oct;44(10):621-8. Epub 2007 Jul 6. Pfendner EG, Vanakker OM, Terry SF, Vourthis S, McAndrew PE, McClain MR, Fratta S, Marais AS, Hariri S, Coucke PJ, Ramsay M, Viljoen D, Terry PF, De Paepe A, Uitto J, Bercovitch LG
Mutation detection in the ABCC6 gene and genotype-phenotype analysis in a large international case series affected by pseudoxanthoma elasticum.
J Med Genet. 2007 Oct;44(10):621-8. Epub 2007 Jul 6., [PMID:17617515]
Abstract [show]
BACKGROUND: Pseudoxanthoma elasticum (PXE), an autosomal recessive disorder with considerable phenotypic variability, mainly affects the eyes, skin and cardiovascular system, characterised by dystrophic mineralization of connective tissues. It is caused by mutations in the ABCC6 (ATP binding cassette family C member 6) gene, which encodes MRP6 (multidrug resistance-associated protein 6). OBJECTIVE: To investigate the mutation spectrum of ABCC6 and possible genotype-phenotype correlations. METHODS: Mutation data were collected on an international case series of 270 patients with PXE (239 probands, 31 affected family members). A denaturing high-performance liquid chromatography-based assay was developed to screen for mutations in all 31 exons, eliminating pseudogene coamplification. In 134 patients with a known phenotype and both mutations identified, genotype-phenotype correlations were assessed. RESULTS: In total, 316 mutant alleles in ABCC6, including 39 novel mutations, were identified in 239 probands. Mutations were found to cluster in exons 24 and 28, corresponding to the second nucleotide-binding fold and the last intracellular domain of the protein. Together with the recurrent R1141X and del23-29 mutations, these mutations accounted for 71.5% of the total individual mutations identified. Genotype-phenotype analysis failed to reveal a significant correlation between the types of mutations identified or their predicted effect on the expression of the protein and the age of onset and severity of the disease. CONCLUSIONS: This study emphasises the principal role of ABCC6 mutations in the pathogenesis of PXE, but the reasons for phenotypic variability remain to be explored.
Comments [show]
None has been submitted yet.
No. Sentence 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.
X
ABCC6 p.Arg1314Gln 17617515:262:3035
status: NEW[hide] [Pseudoxanthoma elasticum]. Ophthalmologe. 2006 Jun;103(6):537-51; quiz 552-3. Ladewig MS, Gotting C, Szliska C, Issa PC, Helb HM, Bedenicki I, Scholl HP, Holz FG
[Pseudoxanthoma elasticum].
Ophthalmologe. 2006 Jun;103(6):537-51; quiz 552-3., [PMID:16763870]
Abstract [show]
Pseudoxanthoma elasticum (PXE) is an inherited disorder that is associated with accumulation of mineralized and fragmented elastic fibers in the skin, vessel walls, and Bruch's membrane. Clinically, patients exhibit characteristic lesions of the skin (soft, ivory-colored papules in a reticular pattern that predominantly affect the neck), the posterior segment of the eye (peau d'orange, angioid streaks, choroidal neovascularizations), and the cardiovascular system (peripheral arterial occlusive disease, coronary occlusion, gastrointestinal bleeding). There is no causal therapy. Recent studies suggest that PXE is inherited almost exclusively as an autosomal recessive trait. Its prevalence has been estimated to be 1:25,000-100,000. The ABCC6 gene on chromosome 16p13.1 is associated with the disease. Mutations within the ABCC6 gene cause reduced or absent transmembraneous transport that leads to accumulation of substrate and calcification of elastic fibers. Although based on clinical features the diagnosis appears readily possible, variability in phenotypic expressions and the low prevalence may be responsible that the disease is underdiagnosed. This review covers current knowledge of PXE and presents therapeutic approaches.
Comments [show]
None has been submitted yet.
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.
X
ABCC6 p.Arg1314Gln 16763870:272:1445
status: NEW[hide] Mutational analysis of the ABCC6 gene and the prox... Hum Mutat. 2006 Aug;27(8):831. Schulz V, Hendig D, Henjakovic M, Szliska C, Kleesiek K, Gotting C
Mutational analysis of the ABCC6 gene and the proximal ABCC6 gene promoter in German patients with pseudoxanthoma elasticum (PXE).
Hum Mutat. 2006 Aug;27(8):831., [PMID:16835894]
Abstract [show]
Pseudoxanthoma elasticum (PXE) is a genetic disorder characterized by calcification of elastic fibers in dermal, ocular, and cardiovascular tissues. Recently, ABCC6 mutations were identified as causing PXE. In this follow-up study we report the investigation of 61 German PXE patients from 53 families, hitherto the largest cohort of German PXE patients screened for the complete ABCC6 gene. In addition, we characterized the proximal ABCC6 promoter of PXE patients according to mutation. In this study we identified 32 disease-causing ABCC6 variants, which had been described previously by us and others, and 10 novel mutations (eight missense mutations and two splice site alterations). The mutation detection rate among index patients was 87.7%. Frequent alterations were the PXE-mutations p.R1141X, Ex23,_Ex29del, and c.2787+1G > T. In the ABCC6 promoter we found the polymorphisms c.-127C > T, c.-132C > T, and c.-219A > C. The difference in the c.-219A > C frequencies between PXE patients and controls were determined as statistically significant. Interestingly, c.-219A > C is located in a transcriptional activator sequence of the ABCC6 promoter and occurred in a binding site for a transcriptional repressor, predominantly found in genes that participate in lipid metabolism. Obtaining these genetic data signifies our contribution to elucidating the pathogenetics of PXE.
Comments [show]
None has been submitted yet.
No. Sentence 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.
X
ABCC6 p.Arg1314Gln 16835894:82:1906
status: NEW89 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.
X
ABCC6 p.Arg1314Gln 16835894:89:1280
status: NEW[hide] Development of a rapid, reliable genetic test for ... J Mol Diagn. 2007 Feb;9(1):105-12. Shi Y, Terry SF, Terry PF, Bercovitch LG, Gerard GF
Development of a rapid, reliable genetic test for pseudoxanthoma elasticum.
J Mol Diagn. 2007 Feb;9(1):105-12., [PMID:17251343]
Abstract [show]
Mutations in the human ABCC6 gene cause pseudoxanthoma elasticum (PXE), a hereditary disorder that impacts the skin, eyes, and cardiovascular system. Currently, the diagnosis of PXE is based on physical findings and histological examination of a biopsy of affected skin. We have combined two simple, polymerase chain reaction (PCR)-based methods to develop a rapid, reliable genetic assay for the majority of known PXE mutations. After PCR amplification and heteroduplex formation, mutations in exon 24 and exon 28 of the ABCC6 gene were detected with Surveyor nuclease, which cleaves double-stranded DNA at any mismatch site. Mutations originating from deletion of a segment of the ABCC6 gene between exon 23 and exon 29 (ex23_ex29del) were detected by long-range PCR. Size analysis of digestion fragments and long-range PCR products was performed by agarose gel electrophoresis. The methods accurately identified mutations or the absence thereof in 16 affected individuals as confirmed by DNA sequencing. Fifteen patients had one or two point mutations, and two of these individuals carried the ex23_ex29del in their second allele. This mutation detection and mapping strategy provides a simple and reliable genetic assay to assist in diagnosis of PXE, differential diagnosis of PXE-like conditions, and study of PXE genetics.
Comments [show]
None has been submitted yet.
No. Sentence 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.
X
ABCC6 p.Arg1314Gln 17251343:82:352
status: NEW[hide] Parameters of oxidative stress are present in the ... Biochim Biophys Acta. 2008 Jul-Aug;1782(7-8):474-81. Epub 2008 May 10. Garcia-Fernandez MI, Gheduzzi D, Boraldi F, Paolinelli CD, Sanchez P, Valdivielso P, Morilla MJ, Quaglino D, Guerra D, Casolari S, Bercovitch L, Pasquali-Ronchetti I
Parameters of oxidative stress are present in the circulation of PXE patients.
Biochim Biophys Acta. 2008 Jul-Aug;1782(7-8):474-81. Epub 2008 May 10., [PMID:18513494]
Abstract [show]
Pseudoxanthoma elasticum (PXE) is an inherited disorder characterized by calcification of elastic fibres leading to dermatological and vascular alterations associated to premature aged features and to life threatening clinical manifestations. The severity of the disease is independent from the type of mutation in the ABCC6 gene, and it has been suggested that local and/or systemic factors may contribute to the occurrence of clinical phenotype. The redox balance in the circulation of 27 PXE patients and of 50 healthy subjects of comparable age was evaluated by measuring the advanced oxidation protein products (AOPP), the lipid peroxidation derivatives (LOOH), the circulating total antioxidant status (TAS), the thiol content and the extracellular superoxide dismutase activity (EC-SOD). Patients were diagnosed by clinical, ultrastructural and molecular findings. Compared to control subjects, PXE patients exhibited significantly lower antioxidant potential, namely circulating TAS and free thiol groups, and higher levels of parameters of oxidative damage, as LOOH and of AOPP, and of circulating EC-SOD activity. Interestingly, the ratio between oxidant and antioxidant parameters was significantly altered in PXE patients and related to various score indices. This study demonstrates, for the first time, that several parameters of oxidative stress are modified in the blood of PXE patients and that the redox balance is significantly altered compared to control subjects of comparable age. Therefore, in PXE patients the circulating impaired redox balance may contribute to the occurrence of several clinical manifestations in PXE patients, and/or to the severity of disease, thus opening new perspectives for their management.
Comments [show]
None has been submitted yet.
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.
X
ABCC6 p.Arg1314Gln 18513494:74:1312
status: NEW