ATP2A2 mutations in Darier's disease: variant cutaneous phenotypes are associated with missense mutations, but neuropsychiatric features are independent of mutation class

Darier's disease (DD) is an autosomal dominant skin disorder characterized clinically by multiple keratotic papules, and histologically by focal loss of adhesion between epidermal cells (acantholysis) and by abnormal keratini zation, Variant forms of cutaneous phenotype, sometimes familial, have been described. Associated neuropsychiatric features, including mental handicap , schizophrenia, bipolar disorder and epilepsy, have also been reported. Th e cause of DD was shown recently to be mutation in the ATP2A2 gene at 12q24 .1, which encodes the sarco-endoplasmic reticulum calcium ATPase type 2 (SE RCA2), Here, we show that while both common isoforms of SERCA2 are expresse d in the cytoplasm of cultured keratinocytes and fibroblasts, in adult skin sections only the longer isoform, SERCA2b, was expressed abundantly in epi dermal structures. Extended mutation analysis in European DD patients using single-strand conformation polymorphism and/or direct sequencing identifie d 40 different patient-specific mutations in 47 families. The majority (23/ 40) were likely to result in nonsense-mediated RNA decay. The remaining 17 were missense mutations distributed throughout the protein and were associa ted significantly with atypical clinical features. The dearest association was with the familial haemorrhagic variant where all four families tested h ad a missense mutation. Three of the families (one Scottish family and two unrelated Italian families) exhibited the same N767S substitution in the M5 transmembrane domain, and a fourth family, from Sweden, had a C268F substi tution in the M3 transmembrane domain. Neuropsychiatric features did not ap pear to be associated with a specific class of mutation and may be an intri nsic, but inconsistent, effect of defective ATP2A2 expression.