Human Molecular Genetics, 1999, Vol. 8, No. 9 1631-1636
© 1999 Oxford University Press
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ATP2A2 mutations in Darier’s disease and their relationship to neuropsychiatric phenotypes
1Neuropsychiatric Genetics Unit, Division of Psychological Medicine, Tenovus Building, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK, 2Department of Dermatology, Churchill Hospital, Oxford OX3 7LJ, UK, 3Washington University School of Medicine, 660 South Euclid Avenue, Box 8123, St Louis, MO 63110, USA and 4Division of Neuroscience, University of Birmingham, Queen Elizabeth Psychiatric Hospital, Birmingham B15 2QZ, UK
Darier’s disease (DD) is a rare, dominantly inherited disorder that affects the skin producing a variety of types of lesion. Close examination of lesional DD skin shows the presence of abnormal keratinization (epidermal differentiation) and acantholysis (loss of cohesion) of keratinocytes. A number of clinical studies have described the co-occurrence of various neurological and psychiatric symptoms with DD, including mood disorders, epilepsy, mental retardation and a slowly progressive encephalopathy. A single locus for DD has been mapped to chromosome 12q23–q24.1, and a variety of missense, nonsense, frameshift and splicing mutations in the ATP2A2 gene have been described recently in families with DD. This gene encodes the sarcoplasmic/endoplasmic reticulum calcium-pumping ATPase SERCA2, which has a central role in intracellular calcium signalling. In this study, we performed mutation analysis on ATP2A2 in 19 unrelated DD patients, of whom 10 had neuropsychiatric phenotypes. We identified and verified 17 novel mutations predicting conservative and non-conservative amino acid changes, potential premature translation terminations and potential altered splicing. Our findings confirm that mutations in ATP2A2 are associated with DD. In neuropsychiatric cases, there was a non-random clustering of mutations in the 3" end of the gene (P = 0.01), and a predominance of the missense type (70% versus 38% in DD patients). This supports the hypothesis that the DD gene has pleiotropic effects in brain and that mutations in SERCA2 are implicated in the pathogenesis of neuropsychiatric disorders.
+ To whom correspondence should be addressed. Tel: +44 1222 743248; Fax +44 1222 746554; Email: owenmj{at}cardiff.ac.uk
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