Severe Darier's Disease by Mitochondrial DNA Insertion Causing Nonsense Mutations: In Silico Prediction of a Pathophysiological Mechanism to a Novel Mutation.

Darier's disease (DD) is an autosomal dominant genetic disorder caused by mutations in ATP2A2. Several cases with nonsense ATP2A2 mutations presented mild-to-moderate phenotypes despite the presumed larger deletion sizes of the ATP2A2 protein. Here, we report a case of severe DD caused by a nonsense mutation with a mitochondrial DNA (mtDNA) insertion despite the smaller presumed deletion size of the ATP2A2 protein. In silico analyses of genomic lesions forming non-B DNA structures and sequence homology indicated the contingency of this DNA insertion. Analysis of the three-dimensional structure of the protein predicted no structural disturbance by this insertion. However, the QGRS Mapper algorithm predicted ectopic G-quadruplex formation in the inserted genome, which may possibly reduce ATP2A2 transcription. Consistent with this hypothetical mechanism and possible nonsense-mediated mRNA decay, we identified downregulation of the mtDNA-inserted ATP2A2, which may partially contribute to the severe phenotype in this case. The mtDNA insertions into the human genome are reported to rarely occur, especially in cancers, and only a handful of mtDNA insertions causing genetic diseases are described. This study is the first report to identify mtDNA insertion as a cause of genetic disease in dermatology and demonstrates its pathophysiological mechanism through in silico analyses.