Darier disease (DD) is an autosomal-dominant skin disorder characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization. Recently we constructed a 2.4-Mb, P1-derived artificial chromosome contig spanning the DD candidate region on chromosome 12q23-24.1. After screening several genes that mapped to this region, we identified mutations in the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca2+-ATPase type 2 isoform (SERCA2) and is highly expressed in keratinocytes. Thirteen mutations were identified, including frameshift deletions, in-frame deletions or insertions, splice-site mutations and non-conservative missense mutations in functional domains. Our results demonstrate that mutations in ATP2A2 cause DD and disclose a role for this pump in a Ca2+-signalling pathway regulating cell-to-cell adhesion and differentiation of the epidermis.
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We thank the clinicians and the families who participated; R. Cox and E. Levy for their contribution in the physical mapping and cytogenetic parts of the project; R. Gibbs for the freely available sequence from the NIH-funded Human Genome Sequencing effort at the Baylor College of Medicine Human Genome Sequencing Center (BCM-HGSC); and J. Bell for support and encouragement. A.S. has a fellowship from the Royal Thai Government and the faculty of Medicine, Ramathibodi Hospital, Mahidol University; S.M. had a Wellcome Trust prize studentship; A.P.M. is a Wellcome Principal Research Fellow; A.H. held a Wellcome Trust and an EC research fellowship. S.C. was supported by a Wellcome Trust Project Grant awarded to T.S., C.S.M. and J.R.; V.R.-P. holds an EC fellowship. The work in Cardiff was supported by grants from the Wellcome Trust. N.C. is a Wellcome Senior Research Fellow.
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