Abstract

Darier disease is an autosomal dominant skin disorder, characterized by follicular and extrafollicular keratotic papules, primarily in seborrheic areas. It is caused by mutations of ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca2+ ATPase isoform 2 (SERCA2 protein). SERCA pumps maintain low cytosolic Ca2+ concentration by actively transporting Ca2+ from the cytosol into the sarco/endoplasmic reticulum. The assembly of desmosomes in epithelial cells in vitro is initiated through an increase in the extracellular Ca2+ concentration but variations in intracellular Ca2+ are also thought to be important. To date, 92 mutations of ATP2A2 gene in Darier disease patients have been identified, scattered throughout the gene. No hotspot mutation has been identified. Considerable phenotypic variations within and between families suggesting that compensatory mechanisms in intracellular Ca2+ homeostasis may include increased expression of the normal ATP2A2 allele and/or compensation by other SERCA pumps (SERCA1 and SERCA3). Alternatively, the activity of SERCA2 pumps required in different cutaneous areas may vary rapid depending on physiological and/or external factors.