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Darier disease (DD) is a rare autosomal dominantly inherited skin disorder caused by mutations in ATP2A2, which is expressed in both the skin and the brain and encodes for SERCA2. We have screened the coding regions of ATP2A2 in a total of 95 unrelated individuals with DD to identify the pathogenic mutations. We identified 66 potentially pathogenic mutations in ATP2A2 for 74 of the 95 individuals with DD of which 45 (68%) are thought to be novel. Forty-nine (74%) are unique to an individual and 17 (26%) were found in more than one individual or overlap with previously identified variants. The results suggest that mutations in ATP2A2 may not be as family-specific as first thought. The spectrum of mutations identified will inform understanding of the pathogenesis of DD., (© 2013 Japanese Dermatological Association.)

Darier's disease is an autosomal dominantly inherited skin disorder characterized by loss of adhesion between epidermal cells, breakdown of desmosome-keratin filaments, and abnormal keratinization. ATP2A2 has been identified as the causative gene of Darier's disease. This gene encodes the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) isoform 2 pump, which transports Ca2+ from the cytosol into the endoplasmic reticulum lumen to maintain a low cytosolic Ca2+ concentration. Using indirect immunofluorescence and biochemical analysis, we investigated the distribution of key desmosomal proteins in normal human and Darier's disease keratinocytes under various calcium conditions. We show that inhibition of SERCA by thapsigargin in normal human keratinocytes impairs the trafficking of the desmoplakins, desmoglein, and desmocollin to the cell surface; these proteins show a diffuse cytoplasmic distribution and, together with plakoglobin, form detergent-insoluble aggregates. In Darier's disease keratinocytes, only the trafficking of desmoplakin is significantly inhibited; in these cells, desmoplakin forms insoluble aggregates when extracted with mild detergent. In contrast, the transmembrane proteins desmoglein and desmocollin are efficiently transported to the cell surface. These proteins, along with plakoglobin, remain equally distributed between detergent-soluble and -insoluble fractions. We also demonstrate an interaction between SERCA2 and desmoplakin during differentiation. Our results provide further insights into the critical role of calcium ATPases in maintaining epidermal integrity.

Darier's disease is a rare cutaneous disease with an autosomal dominant mode of inheritance. Greasy papules and plaques arise on the seborrheic areas and in the flexures and almost all patients have nail abnormalities. Acantholysis and dyskeratosis are the typical histological findings. The underlying defect is a result of mutations in the ATP2A2 gene on chromosome 12q23-24 that encodes for a sarco/endoplasmic reticulum calcium ATPase (SERCA 2). Acantholysis is thought to result from desmosome breakdown. Darier's disease is an example of a dominantly inherited disease caused by haplo-insufficiency. Oral retinoids are the most effective treatment but their adverse effects are troublesome. Topical retinoids, topical corticosteroids, surgery, and laser surgery have their advocates but evidence for efficacy is sparse.