title: Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease.
abstract: Hailey-Hailey disease (HHD, MIM 16960) is inherited in an autosomal dominant manner and characterized by persistent blisters and erosions of the skin. Impaired intercellular adhesion and epidermal blistering also occur in individuals with pemphigus (which is due to autoantibodies directed against desmosomal proteins) and in patients with Darier disease (DD, MIM 124200), which is caused by mutations in a gene encoding a sarco/endoplasmic reticulum (ER)-Golgi calcium pump. We report here the identification of mutations in ATP2C1, encoding the human homologue of an ATP-powered pump that sequesters calcium into the Golgi in yeast, in 21 HHD kindreds. Regulation of cytoplasmic calcium is impaired in cultured keratinocytes from HHD patients, and the normal epidermal calcium gradient is attenuated in vivo in HHD patients. Our findings not only provide an understanding of the molecular basis of HHD, but also underscore the importance of calcium control to the functioning of stratified squamous epithelia.
authors.affiliation: Department of Dermatology, San Francisco General Hospital, University of California at San Francisco, San Francisco, California, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Hu
authors.forename: J M
authors.initials: JM
authors.lastname: Bonifas
authors.forename: J
authors.initials: J
authors.lastname: Beech
authors.forename: G
authors.initials: G
authors.lastname: Bench
authors.forename: T
authors.initials: T
authors.lastname: Shigihara
authors.forename: H
authors.initials: H
authors.lastname: Ogawa
authors.forename: S
authors.initials: S
authors.lastname: Ikeda
authors.forename: T
authors.initials: T
authors.lastname: Mauro
authors.forename: E H
authors.initials: EH
authors.lastname: Epstein
mesh_terms: D000328:Adult; D001483:Base Sequence; D000252:Calcium-Transporting ATPases / Q000235:genetics*; D002454:Cell Differentiation; D002478:Cells, Cultured; D018244:Chromosomes, Artificial, Yeast; D004247:DNA; D005260:Female; D006801:Humans; D006822:Hybrid Cells; D015603:Keratinocytes / Q000166:cytology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D016506:Pemphigus, Benign Familial / Q000235:genetics* / Q000473:pathology
chemical_list: D004247:DNA; C403624:ATP2C1 protein, human; D000252:Calcium-Transporting ATPases