期刊
JOURNAL OF MEDICAL GENETICS
卷 44, 期 10, 页码 621-628出版社
BMJ PUBLISHING GROUP
DOI: 10.1136/jmg.2007.051094
关键词
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资金
- NIAMS NIH HHS [R01AR52627, R01AR28450, R01 AR028450, R01 AR052627] Funding Source: Medline
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.
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