title: Four novel ATP2A2 mutations in Slovenian patients with Darier disease.
abstract: BACKGROUND
  Darier disease (DD) is an autosomal dominant genodermatosis caused by mutations in the ATP2A2 gene. It has been reported that depletion of Ca(2+) stores within the endoplasmic reticulum of keratinocytes is associated with impaired cell cycle regulation and terminal differentiation. Mechanical stress, heat, or UV irradiation might delay cell cycle exit and permit progression into the quiescent stage without repair. When there is associated DNA damage, this can lead to an accumulation of secondary somatic mutations and possible clonal proliferation of damaged keratinocyes within keratotic papules and plaques.
  
  
  OBJECTIVE
  We sought to present clinical, demographic, and genetic analysis of the cohort of Slovenian patients with DD, which represents 52% of DD patients in the country.
  
  
  METHODS
  We examined 28 Slovenians with DD and screened genomic DNA for ATP2A2 mutations and RNA for splice site mutations.
  
  
  RESULTS
  The estimated prevalence of the disease in Slovenia is 2.7/100.000. We identified 7 different ATP2A2 mutations, 4 of which are novel: A516P, R559G, 463-6del6, and 1762-6del18. We also found two previously described polymorphisms in intron XVIII (2741 + 54 G>A) and in exon 15 (2172 G>A; A724A), with allele frequencies of 64.15% and 11.32%, respectively. There was a history of perceptive deafness in two DD patients from two families.
  
  
  CONCLUSIONS
  Analysis of SERCA2 expression, measurements of Ca(2+) uptake and their influence on desmosomal assembly in vitro would add additional value to the study. Although single-stranded conformational analysis (SSCP) is a common and accepted method for screening for the presence of mutations, it does miss 10% to 20% of mutations.
  
  
  CONCLUSIONS
  We identified 4 novel ATP2A2 mutations in Slovenian patients with DD. Deafness seems to be a new phenotypic characteristic of DD patients.
authors.affiliation: Department of Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. aleksandar.godic@gmail.com
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Godic
authors.forename: Branka
authors.initials: B
authors.lastname: Korosec
authors.forename: Jovan
authors.initials: J
authors.lastname: Miljković
authors.forename: Aleksej
authors.initials: A
authors.lastname: Kansky
authors.forename: Damjan
authors.initials: D
authors.lastname: Glavac
mesh_terms: D000328:Adult; D000368:Aged; D007644:Darier Disease / Q000235:genetics*; D003638:Deafness / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics*; D017524:Slovenia
chemical_list: D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; C506946:ATP2A2 protein, human