title: Mutations in the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase isoform cause Darier's disease.
abstract: Darier's disease is an autosomal dominantly inherited skin disorder, characterized by loss of adhesion between epidermal cells and abnormal keratinization. ATP2A2 encoding the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA)2 has been identified as the defective gene in Darier's disease. All mutations previously reported occur in the region of ATP2A2 encoding both SERCA2a and SERCA2b isoforms. These isoforms result from alternative splicing of exon 20, with SERCA2b being the major isoform expressed in the epidermis. In this report, we studied a family affected with Darier's disease and identified a deletion (2993delTG) in a region of exon 20 of ATP2A2, which is specific for SERCA2b. This heterozygous mutation predicts a frameshift with a premature termination codon (PTC+32aa) in the eleventh transmembrane domain of SERCA2b. It segregates with the disease phenotype in the family members tested, and functional analysis shows a drastic reduction of the expression of the mutated protein in comparison with the wild-type SERCA2b. Our result suggests that the mutated allele causes the disease phenotype through loss of function of SERCA2b isoform. This finding indicates that SERCA2b plays a key role in the biology of the epidermis, and its defects are sufficient to cause Darier's disease.
authors.affiliation: The Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, UK.
authors.forename: Jittima
authors.initials: J
authors.lastname: Dhitavat
authors.forename: Leonard
authors.initials: L
authors.lastname: Dode
authors.forename: Natalie
authors.initials: N
authors.lastname: Leslie
authors.forename: Anavaj
authors.initials: A
authors.lastname: Sakuntabhai
authors.forename: Gérard
authors.initials: G
authors.lastname: Lorette
authors.forename: Alain
authors.initials: A
authors.lastname: Hovnanian
mesh_terms: D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D007644:Darier Disease / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D005192:Family Health; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D017434:Protein Structure, Tertiary; D012519:Sarcoplasmic Reticulum / Q000201:enzymology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
chemical_list: D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human; D000252:Calcium-Transporting ATPases; D002118:Calcium