Spectrum of novel ATP2A2 mutations in patients with Darier's disease

被引:132
作者
Sakuntabhai, A
Burge, S
Monk, S
Hovnanian, A
机构
[1] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England
[2] Churchill Hosp, Dept Dermatol, Oxford OX3 7LJ, England
基金
英国惠康基金;
关键词
D O I
10.1093/hmg/8.9.1611
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Darier's disease (DD) is an autosomal dominantly inherited skin disorder characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization. Recently, we identified ATP2A2 encoding the sarco/endoplasmic reticulum Ca2+ ATPase isoform 2 as the defective gene in DD. Now we report a spectrum of ATP2A2 mutations in 19 families and six sporadic cases with DD and investigate genotype-phenotype correlations. All 21 exons and flanking intron boundaries were amplified and screened for mutations by conformation-sensitive gel electrophoresis and direct sequencing. We identified 24 novel mutations that are scattered throughout the ATP2A2 gene. Two families shared an identical mutation on a common disease-associated haplotype, suggesting inheritance from a common ancestor. The majority of the mutations (54%; 13/24) led to a premature termination codon which further supports the proposal that haploinsufficiency is a common molecular mechanism for DD. Thirty-eight per cent of mutations (9/24) result in nonconservative amino acid substitutions at highly conserved positions. Two mutations predict mutated polypeptides lacking or carrying additional amino acids. Marked inter- and intrafamilial phenotypic variability of the disease was observed. These results illustrate the considerable diversity of A TP2A2 mutations causing DD and suggest that additional factors are important contributors to the clinical phenotype.
引用
收藏
页码:1611 / 1619
页数:9
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