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

Darier's disease (DD) is an autosomal dominantly inherited skin disorder ch aracterized 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. No w 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 b y conformation-sensitive gel electrophoresis and direct sequencing. We iden tified 24 novel mutations that are scattered throughout the ATP2A2 gene. Tw o families shared an identical mutation on a common disease-associated hapl otype, suggesting inheritance from a common ancestor. The majority of the m utations (54%; 13/24) led to a premature termination codon which further su pports the proposal that haploinsufficiency is a common molecular mechanism for DD. Thirty-eight per cent of mutations (9/24) result in nonconservativ e amino acid substitutions at highly conserved positions. Two mutations pre dict mutated polypeptides lacking or carrying additional amino acids. Marke d inter- and intrafamilial phenotypic variability of the disease was observ ed. These results illustrate the considerable diversity of A TP2A2 mutation s causing DD and suggest that additional factors are important contributors to the clinical phenotype.