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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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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.
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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