Steady-state and rapid kinetic studies were conducted to functionally characterize the overall and partial reactions of the Ca 2؉ transport cycle mediated by the human sarco(endo)plasmic reticulum Ca 2؉ -ATPase 2 (SERCA2) isoforms, SERCA2a Sarco(endo)plasmic reticulum Ca 2ϩ -ATPases (SERCAs) 1 are single-subunit integral membrane P-type ATPases that mediate the ATP-driven transport of cytosolic Ca 2ϩ against a concentration gradient into the lumen of intracellular Ca 2ϩ -releasable stores such as sarcoplasmic and endoplasmic reticulum (1-4). SERCAs belong to the P-type ATPase family distinguished by the obligatory formation of an aspartyl-phosphorylated intermediate as part of their catalytic cycle. The enzyme cycles reversibly between several states (Scheme 1), of which at least E 1 Ca 2 , E 1 ϳP(Ca 2 ), E 2 -P, and E 2 can be experimentally distinguished. The transfer of the ␥-phosphoryl group of ATP to the aspartate (Asp 351 ) of the phosphorylation domain, leading to the ADP-sensitive high energy phosphoenzyme intermediate E 1 ϳP(Ca 2 ), is activated by conformational changes associated with the binding of two calcium ions in exchange for protons (E 2 to E 1 Ca 2 transition). The conversion of this intermediate to the ADP-insensitive low-energy E 2 -P phosphoenzyme intermediate constitutes a crucial rate-limiting step in Ca 2ϩ translocation (1-3). High resolution models for the atomic structure, generated by x-ray crystallography of crystals in E 1 Ca 2 (5) and Ca 2ϩ -free E 2 (6) forms, and extensive mutational studies (1, 7-11) of the 110-kDa SERCA1a enzyme (994 amino acids) have shown that Ca 2ϩ translocation and ATP utilization are coupled through long range intramolecular interactions between the 10-helix membrane-spanning domain, harboring the Ca 2ϩ binding sites, and the large cytosolic head consisting of actuator (A), phosphorylation (P), and nucleotide-binding (N) domains (Fig. 1).The three human SERCA genes (ATP2A1, ATP2A2, and ATP2A3) encode up to a total of 10 isoforms as a result of the alternative splicing of their pre-mRNA (12-16). Mutations in SERCA genes have been recently detected in human diseases such as Brody disease (muscle disorder) for SERCA1 (17) and

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

Darier's disease and Hailey-Hailey disease are autosomal dominantly inherited skin disorders in which desmosomal adhesion between keratinocytes is abnormal. ATP2A2 and ATP2C1 have been identified as the causative genes for Darier's disease and Hailey-Hailey disease, respectively. ATP2A2 encodes the sarco(endo)plasmic reticulum Ca(2+)-ATPase isoform 2 (SERCA2) pump, while ATP2C1 encodes a secretory pathway Ca(2+)/Mn(2+)-ATPase (SPCA1) found in the Golgi apparatus. We review recent work into the function of these pumps in human keratinocytes and discuss how mutations in these genes might cause these diseases by altering the formation or stability of desmosomes.