title: Darier disease--novel mutations in ATP2A2 and genotype-phenotype correlation.
abstract: Darier disease (DD) is with a frequency of up to 1 in 36,000 a relatively common genodermatosis with autosomal dominant inheritance and late age of onset. The progressive skin manifestations are variable, but often debilitating and disfiguring, and may be associated with a wide range of neuropsychiatric problems, such as epilepsy and depression. On histology, acantholysis and dyskeratosis are prominent findings, implicating impaired functionality of desmosomes. Recently, mutations in the ATP2A2 gene encoding SERCA2, a calcium pump of the endo/sacrcoplasmic reticulum, have been identified as the molecular basis of DD. This slow-twitched calcium ATPase has two splice variants, one of which is highly expressed in epidermis, and maintains low intracellular calcium levels by facilitating transport of cytosolic calcium into the endoplasmic reticulum. Thus, it may confer a direct effect on the established calcium-dependent assembly of desmosomes. We screened ATP2A2 in a cohort of 24 DD families using conformation sensitive gel electrophoresis and direct sequencing, and detected 14 distinct mutations, 9 of which were novel. The mutational spectrum included 9 missense mutations, 1 nonsense mutation, 3 small in-frame deletions, and a 19-basepair insertion. Mutations were scattered over the entire gene with a slight preponderance in the first 8 exons, and affected exclusively residues conserved among all SERCAs. In addition, we found 2 silent polymorphisms, 1 of which occurred in 4 unrelated families. Comparison of molecular data and phenotypic features, such as severity and type of disease, occurrence of mucosal involvement, or association with neuropsychiatric disorders, did not reveal an obvious genotype-phenotype correlation in our cohort.
authors.affiliation: Department of Dermatology and Cutaneous Biology, Jefferson Medical College and Institute of Molecular Medicine, Philadelphia, PA, USA.
authors.forename: F
authors.initials: F
authors.lastname: Ringpfeil
authors.forename: A
authors.initials: A
authors.lastname: Raus
authors.forename: J J
authors.initials: JJ
authors.lastname: DiGiovanna
authors.forename: B
authors.initials: B
authors.lastname: Korge
authors.forename: W
authors.initials: W
authors.lastname: Harth
authors.forename: C
authors.initials: C
authors.lastname: Mazzanti
authors.forename: J
authors.initials: J
authors.lastname: Uitto
authors.forename: S J
authors.initials: SJ
authors.lastname: Bale
authors.forename: G
authors.initials: G
authors.lastname: Richard
mesh_terms: D000252:Calcium-Transporting ATPases / Q000235:genetics*; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000737:chemistry; D007644:Darier Disease / Q000235:genetics* / Q000473:pathology; D004587:Electrophoresis, Agar Gel; D005838:Genotype; D006801:Humans; D007527:Isoenzymes / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D016133:Polymerase Chain Reaction; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
chemical_list: D017931:DNA Primers; D007527:Isoenzymes; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human; D000252:Calcium-Transporting ATPases