Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease

Darier disease (DD) is an autosomal-dominant skin disorder characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal kerat inization. Recently we constructed a 2.4-Mb, Pi-derived artificial chromoso me 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+-ATP ase type 2 isoform (SERCA2) and is highly expressed in keratinocytes. Thirt een mutations were identified, including frameshift deletions. in-frame del etions or insertions, splice-site mutations and non-conservative missense m utations in functional domains. Our results demonstrate that mutations in A TP2A2 cause DD and disclose a role for this pump in a Ca2+-signalling pathw ay regulating cell-to-cell adhesion and differentiation of the epidermis.