title: ATP2A2 mutations in Darier's disease: variant cutaneous phenotypes are associated with missense mutations, but neuropsychiatric features are independent of mutation class.
abstract: Darier's disease (DD) is an autosomal dominant skin disorder characterized clinically by multiple keratotic papules, and histologically by focal loss of adhesion between epidermal cells (acantholysis) and by abnormal keratinization. Variant forms of cutaneous phenotype, sometimes familial, have been described. Associated neuropsychiatric features, including mental handicap, schizophrenia, bipolar disorder and epilepsy, have also been reported. The cause of DD was shown recently to be mutation in the ATP2A2 gene at 12q24.1, which encodes the sarco-endoplasmic reticulum calcium ATPase type 2 (SERCA2). Here, we show that while both common isoforms of SERCA2 are expressed in the cytoplasm of cultured keratinocytes and fibroblasts, in adult skin sections only the longer isoform, SERCA2b, was expressed abundantly in epidermal structures. Extended mutation analysis in European DD patients using single-strand conformation polymorphism and/or direct sequencing identified 40 different patient-specific mutations in 47 families. The majority (23/40) were likely to result in nonsense-mediated RNA decay. The remaining 17 were missense mutations distributed throughout the protein and were associated significantly with atypical clinical features. The clearest association was with the familial haemorrhagic variant where all four families tested had a missense mutation. Three of the families (one Scottish family and two unrelated Italian families) exhibited the same N767S substitution in the M5 transmembrane domain, and a fourth family, from Sweden, had a C268F substitution in the M3 transmembrane domain. Neuropsychiatric features did not appear to be associated with a specific class of mutation and may be an intrinsic, but inconsistent, effect of defective ATP2A2 expression.
authors.affiliation: Human Genetics Unit, School of Biochemistry and Genetics, University of Newcastle upon Tyne, Ridley Building, Claremont Place, Newcastle upon Tyne NE1 7RU, UK.
authors.forename: V L
authors.initials: VL
authors.lastname: Ruiz-Perez
authors.forename: S A
authors.initials: SA
authors.lastname: Carter
authors.forename: E
authors.initials: E
authors.lastname: Healy
authors.forename: C
authors.initials: C
authors.lastname: Todd
authors.forename: J L
authors.initials: JL
authors.lastname: Rees
authors.forename: P M
authors.initials: PM
authors.lastname: Steijlen
authors.forename: A J
authors.initials: AJ
authors.lastname: Carmichael
authors.forename: H M
authors.initials: HM
authors.lastname: Lewis
authors.forename: D
authors.initials: D
authors.lastname: Hohl
authors.forename: P
authors.initials: P
authors.lastname: Itin
authors.forename: A
authors.initials: A
authors.lastname: Vahlquist
authors.forename: T
authors.initials: T
authors.lastname: Gobello
authors.forename: C
authors.initials: C
authors.lastname: Mazzanti
authors.forename: R
authors.initials: R
authors.lastname: Reggazini
authors.forename: G
authors.initials: G
authors.lastname: Nagy
authors.forename: C S
authors.initials: CS
authors.lastname: Munro
authors.forename: T
authors.initials: T
authors.lastname: Strachan
mesh_terms: D000252:Calcium-Transporting ATPases / Q000235:genetics*; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D017931:DNA Primers; D007644:Darier Disease / Q000235:genetics* / Q000473:pathology / Q000523:psychology; D005060:Europe; D006801:Humans; D007150:Immunohistochemistry; D007527:Isoenzymes / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D018807:Polymorphism, Single-Stranded Conformational; D012867:Skin / Q000378:metabolism / Q000473:pathology*
chemical_list: D017931:DNA Primers; D007527:Isoenzymes; D000252:Calcium-Transporting ATPases