ABCC6 p.Ala830Gly
| Predicted by SNAP2: | C: N (87%), D: N (82%), E: N (93%), F: N (53%), G: N (93%), H: N (87%), I: N (93%), K: N (87%), L: N (87%), M: N (93%), N: N (93%), P: N (78%), Q: N (93%), R: N (87%), S: N (97%), T: N (97%), V: N (93%), W: D (59%), Y: N (53%), |
| Predicted by PROVEAN: | C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: D, Y: N, |
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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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159 Table 4 Polymorphic sequence changes identified in ABCC6 Nucleotide Amino acid Location Estimated frequency (%) CA(18) F Intron4 68 V415V 1245G>A 10 33 V614A 1841T>C 14 52 T630T 1890C>G 15 22 H632Q 1896C>A 15 24 A830G 2490C>G 19 25 P945P 2846C>T 22 50 L968L 2904G>A 22 20 Int(22) F Intron22 50 R1268Q 3808G>A 27 38 The definition of disease-associated alleles essentially follows the criteria described by Le Saux et al.22 In summary, sequence variants predicted to result in nonsense or splice-site changes were considered to be disease-associated alleles if they are absent in DNA of a panel of at least 100 controls.
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ABCC6 p.Ala830Gly 12673275:159:212
status: NEW[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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104 Three of these were used in this study to construct the following haplotypes: (1) 1896 C3A in exon 15 predicting an H632Q substitution, (2) 2490 C3G in exon 19 predicting an A830G substitution, and (3) 3803 G3A in exon 27 predicting a R1268Q substitution.
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ABCC6 p.Ala830Gly 12714611:104:174
status: NEW