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X Hu, A Plomp, JB ten Brink, J Wijnholds, EJ Schuurman, S van Soest, M Oud, R Peek, PT V M Jong, AA B Bergen; Molecular analysis of Pseudoxanthoma Elasticum: spectrum of ABCC6 gene mutations in the Netherlands . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2394.
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Purpose: To better understand the function of ABCC6 in the pathogenesis of Pseudoxanthoma Elasticum(PXE) and to direct the service of clinical geneticists for PXE patients by offering the relationship between genotype and phenotype. Methods: The clinical diagnosis of PXE in individuals met all criteria reported by the PXE consensus conference in 1994. The majority of patients are of Dutch descent and were primarily ascertained through the national register of genetic eye diseases at the Netherlands Ophthalmic Research Institute. The ABCC6 gene was screened in 57 unrelated familial and sporadic PXE cases by single strand conformation polymorphism (SSCP), sequencing analysis, and Southern blot. Results: We identified 45 mutation carriers with at least one disease-causing allele, representing 79% of PXE patients studied. A total of 15 different mutations were characterized. All are likely to be causative mutations since by were excluded from 200 control chromosomes. All classes of mutation were detected, including nonsense, missense, frameshift, and splice site mutations. The most mutations create stop codons in the gene, as a consequence, either a shorter mRNA or a truncated protein. Whereas most mutations occur only once, the nonsense mutation R1141X (a C-to-T substitution) within exon 24 accounts for 15 of 45 (33%) of all mutations detected. Seven different missense mutations were found in 10 patients. Four different frameshifting insertions/deletions and one splice site mutation were identified in 15 patients. A deletion spanning exon 23 to 29 in ABCC6 gene was detected in 3 unrelated families. One patient showed compound heterozygous deletions, combining an intragenic exon 23-29 deletion and large intergenic deletion which encompasses ABCC1, ABCC6 and MYH11. Conclusions: Multiple mutations in the ABCC6 gene are associated with PXE. A scan of the entire coding sequencing and duplication part of the gene may be required to detect the causative mutation in PXE patients. It is likely that PXE, in a subset of cases is caused by loss of ABCC6 function.
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