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

Darier disease (DD) is with a frequency of up to 1 in 36,000 a relatively c ommon genodermatosis with autosomal dominant inheritance and late age of on set. The progressive skin manifestations are variable, but often debilitati ng and disfiguring, and may be associated with a wide range of neuropsychia tric 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 c alcium pump of the endo/sacrcoplasmic reticulum, have been identified as th e molecular basis of DD. This slow-twitched calcium ATPase has two splice v ariants, one of which is highly expressed in epidermis, and maintains low i ntracellular 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 electrophoresi s and direct sequencing, and detected 14 distinct mutations, 9 of which wer e novel. The mutational spectrum included 9 missense mutations, 1 nonsense mutation, 3 small in-frame deletions, and a 19-basepair insertion. Mutation s were scattered over the entire gene with a slight preponderance in the fi rst 8 exons, and affected exclusively residues conserved among all SERCAs. In addition, we found 2 silent polymorphisms, 1 of which occurred in 4 unre lated families. Comparison of molecular data and phenotypic features, such as severity and type of disease, occurrence of mucosal involvement, or asso ciation with neuropsychiatric disorders, did not reveal an obvious genotype -phenotype correlation in our cohort.