Mosaicism for ATP2A2 Mutations Causes Segmental Darier's Disease

Abstract

Epidermal naevi are localized malformations of the epidermis consisting of verrucoid scaly papules and plaques following Blaschko's lines. Genetic mosaicism has been proposed to underlie the development of linear epidermal naevi. Rarely, epidermal naevi show acantholytic histology similar to Darier's disease, a dominantly inherited skin condition characterized by widespread warty papules. As patients with acantholytic dyskeratotic naevi often give a history of worsening after sun exposure and the lesions are typical of Darier's disease, numerous authors have proposed that these patients have segmental Darier's disease. The postulated relationship has not been proven, however. Recently, we identified ATP2A2, which encodes the sarco/endoplasmic reticulum Ca(2+) ATPase isoform 2 as the defective gene in Darier's disease. In this report, we investigated the involvement of ATP2A2 in acantholytic dyskeratotic naevi following Blaschko's lines in two patients. We identified a nonsense mutation (Y894X) in the first patient and a nonconservative glycine to arginine mutation at codon 769 (G769R) in the other patient. These mutations were present in affected skin, and were not detected in unaffected skin or in leukocytes. We conclude that acantholytic dyskeratotic naevi can arise from a somatic mutation in ATP2A2. These individuals are mosaics for the mutation, but the risk of transmission of generalized Darier's disease will depend on whether the germline is affected. Our findings provide further evidence that Blaschko's lines do reflect genetic mosaicism and that the term acantholytic dyskeratotic naevus might be replaced in the future by segmental Darier's disease induced by postzygotic mosaicism. J Invest Dermatol 115:1144-1147 2000

Comprehensive Analysis of Expression and Function of 51 Sarco(endo)plasmic Reticulum Ca2+-ATPase Mutants Associated with Darier Disease

“…Mutations in the SERCA2 gene (ATP2A2) and the resulting defects in the SERCA2b housekeeping isoform cause an autosomal dominant genetic skin disease, Darier disease (DD) (11,12). Over 100 mutations have been found with the DD pedigrees (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24). They include many nonsense mutations, and also substitution and deletion mutations of amino acid residues.…”

Darier's disease: hopes and challenges

“…6,7 The mutations responsible for Darier's disease have been located in the ATP2A2 gene on chromosome 12q23-24.1. 8 Mosaicism for ATP2A2 mutations causes segmental Darier's disease. 9 This gene encodes a sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA2), which transports Ca 2+ from the cytosol back to the endoplasmic reticulum lumen.…”

“…8 Mosaicism for ATP2A2 mutations causes segmental Darier's disease. 9 This gene encodes a sarco/endoplasmic reticulum Ca 2+ ATPase (SERCA2), which transports Ca 2+ from the cytosol back to the endoplasmic reticulum lumen. 10 Abnormalities of SERCA2 in Darier's disease may alter cell signalling and affect the synthesis, folding or trafficking of desmosomal components.…”

“…8 Histologically the lesions of Darier's disease show proliferative epidermal 'budding' and dyskeratosis as well as loss of adhesion. Desmosomes may participate in cell signalling and influence cell growth and differentiation.…”

“…14 Unfortunately it is not possible to predict the severity of disease in the offspring of an affected person, and the outcomes of investigations into genotype-phenotype correlations have been disappointing. 8 Considerable variation in severity was found within and between families, and in some patients with classic disease no mutation was identified. Clinical heterogeneity (a range of phenotypes produced by the same mutation) and genetic heterogeneity (identical phenotypes produced by different mutations) are well described in the genodermatoses.…”