Darier disease - Novel mutations in ATP2A2 and genotype-phenotype correlation

F. Ringpfeil, A. Raus, J. J. Digiovanna, B. Korge, W. Harth, C. Mazzanti, J. Uitto, S. J. Bale, G. Richard

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Darier disease (DD) is with a frequency of up to 1 in 36,000 a relatively common genodermatosis with autosomal dominant inheritance and late 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 demosomes. 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 effected 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.

Original languageEnglish
Pages (from-to)19-27
Number of pages9
JournalExperimental Dermatology
Issue number1
Publication statusPublished - 2001



  • Calcium ATPase
  • Keratosis follicularis
  • Mutation

ASJC Scopus subject areas

  • Dermatology

Cite this

Ringpfeil, F., Raus, A., Digiovanna, J. J., Korge, B., Harth, W., Mazzanti, C., Uitto, J., Bale, S. J., & Richard, G. (2001). Darier disease - Novel mutations in ATP2A2 and genotype-phenotype correlation. Experimental Dermatology, 10(1), 19-27. https://doi.org/10.1034/j.1600-0625.2001.100103.x