Mutational analysis of the ATP2A2 gene in two Darier disease families with intrafamilial variability

Summary Background  Darier disease (DD), an autosomal dominant genodermatosis characterized by warty papules and plaques over seborrhoeic areas, is caused by mutations in the ATP2A2 gene, which encodes the sarco/endoplasmic reticulum Ca2+ ATPase type 2 isoform (SERCA2). While markedly different clinical severity within DD-affected family members is known, the pathomechanism has not been elucidated. Objectives  Based on the hypothesis that multiple ATP2A2 mutations might contribute to the pathomechanism, we have analysed two DD families in which the clinical severity differs markedly within a single pedigree, and, as controls, eight DD families without differing clinical severity. Methods  All the exons and intron–exon borders of ATP2A2 were directly sequenced from the genomic DNA extracted from all the subjects. Results  We identified the heterozygous mutations, G233R in pedigree 1 and C318R in pedigree 2, respectively, whereas no other ATP2A2 mutations in any of severely affected individuals were found. In eight DD pedigrees as control, we have found M1V, N39D, L180R, A838P and 2170 insertion G in each of five pedigrees, but no mutation was found in three DD pedigrees. Conclusions  Our results together with previous data indicate that the distribution of mutations is scattered over the entire ATP2A2 without any, as yet, discernible ‘hotspots’. The mutations in pedigrees 1 and 2 with intrafamiliar clinical differences occurred around the Ca2+-binding sites on SERCA2, which might be associated with differences in clinical severity. These variations in ATP2A2 mutations alone cannot account for the clinical heterogeneity within DD pedigrees.