title: Spectrum of novel ATP2A2 mutations in patients with Darier's disease.
abstract: 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 Ca(2+)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 haploin-sufficiency is a common molecular mechanism for DD. Thirty-eight per cent of mutations (9/24) result in non-conservative 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 ATP2A2 mutations causing DD and suggest that additional factors are important contributors to the clinical phenotype.
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Headington, Oxford OX3 7BN, UK.
authors.forename: A
authors.initials: A
authors.lastname: Sakuntabhai
authors.forename: S
authors.initials: S
authors.lastname: Burge
authors.forename: S
authors.initials: S
authors.lastname: Monk
authors.forename: A
authors.initials: A
authors.lastname: Hovnanian
mesh_terms: D000252:Calcium-Transporting ATPases / Q000235:genetics*; D004252:DNA Mutational Analysis; D007644:Darier Disease / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D005060:Europe; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000473:pathology
chemical_list: D007527:Isoenzymes; D000252:Calcium-Transporting ATPases