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Darier disease (DD) is a rare skin condition with autosomal dominant inheritance that manifests in childhood or adolescence (1, 2). It is characterized by keratotic papules that may coalesce into large warty plaques, predominantly affecting seborrhoeic areas, such as the forehead, central chest, back and scalp borders, usually accompanied by palmoplantar pits and characteristic nail changes (i.e. longitudinal leukonychia and V-shaped notches at the distal end of the nail plate) (1, 3). Involvement of intertriginous areas and psychiatric symptoms may also be present (1, 3). Heat or humidity, excessive sweating, exposure to ultraviolet (UV) light, friction, medications and infections, as well as pregnancy or delivery, aggravate the disorder (3). Histologically, DD is characterized by loss of adhesion between epidermal cells, termed acantholysis, leading to suprabasal cleavage and abnormal keratinization, which manifests as corps ronds and grains (4). DD is caused by mutations in the ATP2A2 gene, which encodes isoforms of the sarco/endoplasmic reticulum ATPase type 2 (SERCA2) in keratinocytes and cells from other tissues (5). SERCA2 is a calcium pump incorporated in the endoplasmic reticulum (ER) membrane that regulates Ca2+ transport from the cytoplasm into the ER lumen. It is organized in 10 transmembrane helices (M1–M10) intercalated by 5 stalk sectors (S1–S5), and in a cytosolexposed region comprising the phosphorylation and ATP-binding domains (5). In 2000, genetic mosaicism for mutations in ATP2A2 was demonstrated to cause the segmental form of the disease (6), which is quite rare. Segmental DD can manifest in a mosaic pattern distinctive of 2 disease subtypes: segmental DD type 1, which is characterized by warty papules distributed in a linear pattern on a background of clinically normal skin, and segmental DD type 2, in which linear DD lesions are usually more severe and may manifest early after birth, superimposed on a background of generalized DD (7, 8). Segmental DD type 1 was hypothesized to result from a de novo postzygotic ATP2A2 mutation that occurs during embryogenesis, and a few studies have provided genetic proof for this aetiology (4, 9), whereas a loss-of heterozygosity (LOH) in a heterozygous individual was hypothesized for segmental DD type 2 (10). Although there is no direct evidence for LOH as a causal event for DD type 2, molecular genetic support has been provided (8). We report here on the molecular basis of the mosaicism in an Italian woman with segmental DD type 1.

A Postzygotic ATP2A2 Novel Mutation Identified by Next-generation Sequencing in Mosaic Darier Disease