Human Molecular Genetics, 1999, Vol. 8, No. 9 1621-1630
© 1999 Oxford University Press
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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
Human Genetics Unit, School of Biochemistry and Genetics, University of Newcastle upon Tyne, Ridley Building, Claremont Place, Newcastle upon Tyne NE1 7RU, UK, 1Department of Dermatology, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, UK, 2University Hospital Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands, 3South Cleveland Hospital, Middlesborough, Cleveland TS34 3BW, UK, 4Selly Oak Hospital, Raddlebarn Road, Birmingham B29 6JD, UK, 5CHUV-DHURDV, CH-1011 Lausanne, Switzerland, 6University Hospital of Basel, Petergraben 4, CH-4031 Basel, Switzerland, 7University Hospital, SE-751 85 Uppsala, Sweden, 8Istituto Dermatopatica dell’Immacolata, Via Monte di Creta 104, Roma, Italy, 9Ospedale Santa Anna, Como, Italy, 10Kaposi Mór"" Megyei Kórház, Gróf Apponyi Albert u. 16, Kaposvár, H-7400 Hungary and 11Southern General Hospital, Glasgow G51 4TF, UK
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.
+ To whom correspondence should be addressed. T.S.—Tel: +44 191 222 8855; Fax: +44 191 222 6662; Email: tom.strachan{at}ncl.ac.uk C.S.M.—Tel: +44 141 201 1100; Fax: +44 141 201 2989; Email: c.s.munro@clinmed.gla.ac.uk
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