ABCMdb

ABCC6 p.Arg1459Cys

ClinVar:	c.4375C>T , p.Arg1459Cys D , Pathogenic
LOVD-ABCC6:	p.Arg1459Cys 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: D (95%), S: D (95%), T: D (95%), V: D (95%), W: D (95%), 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,

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[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.

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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
43 We found eight different missense mutations (R765Q, R1114H, T1130M, R1221C, A1303P, G1302R, K1394N, R1459C) that occurred in various combinations in nine alleles of eight patients. 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
96 Figure 3 RT-PCR analysis of ABCC6 expression in leukcocytes in individuals homozygous and heterozygous for the R114X mutation and in individuals heterozygous for the R1459C mutation compared with wild-type ABCC6. Login to comment
104 We detected an ABCC6/ MRP6 missense mutation (R1459C) heterozygously present in the DNA and RNA of all affected individuals. Login to comment
107 Restriction analysis of an RT-PCR product of exon 30 revealed the presence of the R1459C mutation in one transcript, while the other transcript was wild type (Figure 3). Login to comment
108 Sequencing of the entire ABCC6 cDNA in two patients (II-2, II-7) through RT-PCR of RNA from peripheral blood showed the presence of a mutated (R1459C), as well as an entirely normal, wild-type ABCC6 transcript, without mutations (not shown). Login to comment
109 We found the R1459C mutation also in the DNA of a maternal nephew, who, unfortunately, refused clinical examination (not shown). Login to comment
110 However, the latter finding provides further evidence that the R1459C mutation in this pedigree segregates via the maternal line to the affected children. 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
138 In this study, we presented a novel family with an R1459C ABCC6/MRP6 mutation, in which ad segregation of PXE on the basis of clinical, molecular, and genealogical data, is the most likely explanation for our results. 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

[hide] Analysis of the frequent R1141X mutation in the AB... Invest Ophthalmol Vis Sci. 2003 May;44(5):1824-9. Hu X, Peek R, Plomp A, ten Brink J, Scheffer G, van Soest S, Leys A, de Jong PT, Bergen AA
Analysis of the frequent R1141X mutation in the ABCC6 gene in pseudoxanthoma elasticum.
Invest Ophthalmol Vis Sci. 2003 May;44(5):1824-9., [PMID:12714611]

Abstract [show]
PURPOSE: 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). METHODS: A combination of single-strand conformational polymorphism (SSCP), PCR, sequencing, and Southern blot analysis was used to identify mutations in the ABCC6 gene in 62 patients. Haplotypes of 16 patients with the R1141X mutation were determined with eight polymorphic markers spanning the ABCC6 locus. 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. ABCC6 expression was analyzed by RT-PCR and immunocytochemistry with ABCC6-specific monoclonal antibodies. RESULTS: The ABCC6 R1141X mutation was found on 19 alleles in 16 patients with PXE and occurred in heterozygous, homozygous, or compound heterozygous form. All R1141X alleles were associated with a common haplotype, covering at least three intragenic ABCC6 markers. None of the patients or healthy control subjects had a similar ABCC6 haplotype. 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. 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. CONCLUSIONS: A specific founder effect for the R1141X mutation exists in Dutch patients with PXE. The R1141X mutation induces instability of the aberrant mRNA. Functional haploinsufficiency or loss of function of ABCC6 caused by mechanisms, such as nonsense-mediated decay (NMD), may be involved in the PXE phenotype.

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126 As a control for the latter analysis, we also determined this ratio in blood cells from a healthy donor and from a patient with PXE heterozygous for a missense mutation R1459C in exon 30 of ABCC6. Login to comment
128 In contrast, the relative amount of mRNA carrying the R1459C mutation (48%) was very similar to that of the wild-type mRNA (52%; Table 3), whereas the cells of a healthy donor contained only wild-type mRNA. 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

[hide] Does autosomal dominant pseudoxanthoma elasticum e... Am J Med Genet A. 2004 May 1;126A(4):403-12. Plomp AS, Hu X, de Jong PT, Bergen AA
Does autosomal dominant pseudoxanthoma elasticum exist?
Am J Med Genet A. 2004 May 1;126A(4):403-12., 2004-05-01 [PMID:15098239]

Abstract [show]
Pseudoxanthoma elasticum (PXE) is a progressive disorder of elastic fibers in skin, eyes, and arterial walls. It is caused by mutations in the ABCC6 gene. Most patients are sporadic cases. The majority of familial cases show autosomal recessive (AR) inheritance, but autosomal dominant (AD) inheritance has also been reported. We reviewed the literature on AD PXE and we studied in detail, both clinically and by DNA studies, a selection of potentially AD pedigrees from our patient population consisting of 59 probands and their family members. Individuals were considered to have definite PXE if they had two of the following three criteria: characteristic ophthalmologic signs, characteristic dermatologic signs, and a positive skin biopsy. In the literature we found only three families with definite PXE in two successive generations and no families with definite PXE in three or more generations. Our own data set comprised three putative AD families. Extensive DNA studies revealed a mutation in only one ABCC6 allele in the patients of these families. Only one of our families showed definite PXE in two generations. Linkage studies revealed that pseudodominance was unlikely in this family. In the other two families AD PXE could not be confirmed after extensive clinical examinations and application of our criteria, since definite PXE was not present in two or more generations. Conclusion: the inheritance pattern in PXE usually is AR. Part of the phenotype in family members of PXE patients might be due to expression in heterozygous carriers of an AR disease. AD inheritance in PXE may exist, but is both after careful literature study and in our patient material much rarer than previously thought.

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153 However, the presence of an R1459C mutation in the ABCC6 gene of a nephew (III-9) suggested that she transmitted this mutation to her affected children (Fig. 4). Login to comment
156 They did not have the R1459C mutation. Login to comment
159 Extensive screening of the ABCC6 gene revealed an R1459C mutation in one allele only. Login to comment
160 Direct sequencing of the entire cDNA, derived from both alleles, showed one mutated (R1459C) and one wild type ABCC6 transcript (not shown). Login to comment
164 He did have the R1459C mutation. Login to comment
177 He also had the R1459C mutation in one allele. Login to comment
181 DNA studies showed the R1459C mutation in one allele. Login to comment
183 ABCC6 transcript analysis showed the presence of one mutated (R1459C) and one wild type allele in all affected family members. Login to comment
269 Our family 3 shows that R1459C might be a mutation that can cause PXE in the heterozygous state. Login to comment

[hide] Efficient molecular diagnostic strategy for ABCC6 ... Genet Test. 2004 Fall;8(3):292-300. Hu X, Plomp A, Gorgels T, Brink JT, Loves W, Mannens M, de Jong PT, Bergen AA
Efficient molecular diagnostic strategy for ABCC6 in pseudoxanthoma elasticum.
Genet Test. 2004 Fall;8(3):292-300., [PMID:15727254]

Abstract [show]
Pseudoxanthoma elasticum (PXE) is a hereditary disorder of connective tissue with skin, cardiovascular, and visual involvement. In familial cases, PXE usually segregates in an autosomal recessive fashion. The aim of this manuscript is to describe an efficient strategy for DNA diagnosis of PXE. 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. Next, in the remaining patient group in which only one or no mutant allele was found, the complete coding sequence was analyzed using denaturing high-performance liquid chromatography (dHPLC). All variations found were confirmed by direct DNA sequencing. Finally, Southern blot was used to investigate the potential presence of small or large deletions. Twenty different mutations, including two novel mutations in the ABCC6 gene, were identified in 80.3% of the 76 patients, and 58.6% of the 152 ABCC6 alleles analyzed. With this strategy, 70 (78.7%) out of 89 mutant alleles could be detected within a week. We conclude that this strategy leads to both reliable and time-saving screening for mutations in the ABCC6 gene in sporadic cases and in families with PXE.

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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
157 Next, R765Q, G1302R, A1303P, 3775 del T, and R1459C mutations were detected in 15 mutant alleles by digestion of PCR fragments with restriction enzymes Sma I, Nci I, Hae III, Bst NI, and Aci I, respectively. Login to comment
214 Our group investigated one family with a missense mutation (R1459C) by genotype, transcript, or haplotype and found no mutation on the second allele of the ABCC6 gene (Hu et al., 2003a; Plomp et al., 2004). Login to comment

[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.

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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

[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.

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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

[hide] Added value of infrared, red-free and autofluoresc... Br J Ophthalmol. 2010 Apr;94(4):479-86. Epub 2009 Sep 1. De Zaeytijd J, Vanakker OM, Coucke PJ, De Paepe A, De Laey JJ, Leroy BP
Added value of infrared, red-free and autofluorescence fundus imaging in pseudoxanthoma elasticum.
Br J Ophthalmol. 2010 Apr;94(4):479-86. Epub 2009 Sep 1., [PMID:19726431]

Abstract [show]
PURPOSE: Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder caused by mutations in the ABCC6 gene and primarily affects the oculocutaneous and cardiovascular systems. However, the phenotype, including the ophthalmological manifestations, varies in severity. The present study aims to evaluate the added value of novel funduscopic imaging techniques, such as near-infrared reflectance, red-free and autofluorescence imaging in PXE. METHODS: In 22 molecularly proven PXE patients and 25 obligate carriers, PXE retinopathy was evaluated using funduscopy, white light, red-free, infrared and autofluorescence imaging. RESULTS: At least one characteristic of PXE retinopathy was evident on funduscopy of all eyes. Angioid streaks could be subdivided in those with (brick red) or without (feathered) adjacent RPE alterations. Infrared imaging showed the brick-red-coloured streaks as well-demarcated dark fissures, even when these passed unnoticed on funduscopy. Feathered types were detected as triangular areas of hypoautofluorescence. The peau d'orange was much more visible and much more widespread on infrared imaging, with extension from the posterior pole towards the whole midperiphery. Comets and comet tails were best seen with red-free imaging. CONCLUSIONS: Infrared, red-free and autofluorescence imaging are more sensitive than white light funduscopy and imaging in visualising early retinal signs of PXE. In addition, this specialised imaging allows a better appreciation of the extent of lesions. Hence, such imaging increases the chances of making a correct diagnosis early, and aids in the accurate evaluation of evolution of disease in the ophthalmic follow-up of PXE patients.

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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

[hide] Analysis of pseudoxanthoma elasticum-causing misse... J Invest Dermatol. 2014 Apr;134(4):946-53. doi: 10.1038/jid.2013.482. Epub 2013 Nov 11. Pomozi V, Brampton C, Fulop K, Chen LH, Apana A, Li Q, Uitto J, Le Saux O, Varadi A
Analysis of pseudoxanthoma elasticum-causing missense mutants of ABCC6 in vivo; pharmacological correction of the mislocalized proteins.
J Invest Dermatol. 2014 Apr;134(4):946-53. doi: 10.1038/jid.2013.482. Epub 2013 Nov 11., [PMID:24352041]

Abstract [show]
Mutations in the ABCC6 gene cause soft-tissue calcification in pseudoxanthoma elasticum (PXE) and, in some patients, generalized arterial calcification of infancy (GACI). PXE is characterized by late onset and progressive mineralization of elastic fibers in dermal, ocular, and cardiovascular tissues. GACI patients present a more severe, often prenatal arterial calcification. We have tested 10 frequent disease-causing ABCC6 missense mutants for the transport activity by using Sf9 (Spodoptera frugiperda) cells, characterized the subcellular localization in MDCKII (Madin-Darby canine kidney (cell line)) cells and in mouse liver, and tested the phenotypic rescue in zebrafish. We aimed at identifying mutants with preserved transport activity but with improper plasma membrane localization for rescue by the chemical chaperone 4-phenylbutyrate (4-PBA). Seven of the mutants were transport-competent but mislocalized in mouse liver. The observed divergence in cellular localization of mutants in MDCKII cells versus mouse liver underlined the limitations of this 2D in vitro cell system. The functionality of ABCC6 mutants was tested in zebrafish, and minimal rescue of the morpholino-induced phenotype was found. However, 4-PBA, a drug approved for clinical use, restored the plasma membrane localization of four ABCC6 mutants (R1114P, S1121W, Q1347H, and R1314W), suggesting that allele-specific therapy may be useful for selected patients with PXE and GACI.

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64 The R1459C and the transport- inactive V1298F mutants were found in subcellular localization identical to the wt, whereas all the other mutants showed various degrees of intracellular localization, as illustrated in Figure 3, column 1. Login to comment
78 Note that this type of experiment was not performed in vivo with the two inactive mutants, V1298F and G1321S, or with R1459C, as this mutant was found in the plasma membrane without 4-PBA treatment. Login to comment
80 For instance, mutants Q1347H and R1459C were found mostly intracellularly in nonpolarized and in polarized MDCKII cells, yet the 4-PBA treatment resulted in plasma membrane localization only when these two variants were expressed in nonpolarized cells. Login to comment
82 No 4-PBA-induced plasma membrane rescue was observed for R1138Q and T1301I in mouse liver, whereas Extracellular Walker B Q-loop Signature Missense mutations Intercellular 140 ABCC6 wt V1298F G1321S R1114P R1138Q R1314W R1459C S1121W T1301I Q1347H delABCC6 120 100 80 60 40 20 0 LTC4 transport activity (%) TMD0 L0 TMD1 L1 TMD2 R1114P S1121W R1138Q T1301I R1314W G1321S R1339C R1459C Q1347H Figure 1. Login to comment
113 MDCKII cell line in vitro Nonpolarized - 4-PBA 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m 20 &#b5;m Wild type R1114P S1121W R1138Q V1298F T1301I R1314W G1321S R1339C Q1347H R1459C deltaABCC6 - 4-PBA + 4-PBA + 4-PBA Not determined Polarized intended to correct their cellular localization, as described previously (Le Saux et al., 2011). Login to comment
114 For both mutants Q1347H and R1459C, the chemical chaperone was effective in correcting its cellular trafficking only in nonpolarized cultures. Login to comment
126 Mouse liver in vivo - 4-PBA Not determined Not determined Not determined Wild type R1114P S1121W R1138Q V1298F T1301I R1314W G1321S R1339C Q1347H R1459C deltaABCC6 + 4-PBA Figure 4. Login to comment
140 In addition, it is noteworthy that the PXE-associated mutant R1459C (Chassaing et al., 2005) was found to be an active transporter, and it localized in the plasma membrane in mouse hepatocytes, suggesting that R1459C could be a neutral polymorphism rather than a disease-causing mutant. Login to comment
142 The case of R1459C illustrates the necessity of using multiple model systems in parallel to study the functional consequences of ABCC6 mutations. 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