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

Lookup NU author(s): Dr Victor Ruiz-Perez, Simon Carter, Dr Eugene Healy, Carole Todd, Professor Jonathan Rees, Professor Tom Strachan

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Abstract

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 keratinization. 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. The 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 (SERCA2). Here, we show that while both common isoforms of SERCA2 are expressed in the cytoplasm of cultured keratinocytes and fibroblasts, in adult skin sections only the longer isoform, SERCA2b, was expressed abundantly in epidermal structures. Extended mutation analysis in European DD patients using single-strand conformation polymorphism and/or direct sequencing identified 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 associated significantly with atypical clinical features. The clearest association was with the familial haemorrhagic variant where all four families tested had 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 substitution in the M3 transmembrane domain. Neuropsychiatric features did not appear to be associated with a specific class of mutation and may be an intrinsic, but inconsistent, effect of defective ATP2A2 expression.

Publication metadata

Author(s): Healy E; Todd C; Strachan T; Ruiz-Perez VL; Rees JL; Carter SA; Itin P; Vahlquist A; Gobello T; Mazzanti C; Reggazini R; Nagy G; Munro CS; Steijlen PM; Carmichael AJ; Lewis HM; Hohl D

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 1999

Volume: 8

Issue: 9

Pages: 1621-1630

Print publication date: 01/09/1999

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/hmg/8.9.1621

DOI: 10.1093/hmg/8.9.1621

PubMed id: 10441324

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