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

## TL;DR

This paper reports a severe case of Darier's disease caused by a rare mitochondrial DNA insertion into the ATP2A2 gene, suggesting a novel pathophysiological mechanism.

## Contribution

The first report of mtDNA insertion causing a dermatological genetic disease with in silico evidence of its pathophysiological mechanism.

## Key findings

- A mitochondrial DNA insertion in ATP2A2 was identified in a severe Darier's disease case.
- In silico analysis suggests the insertion may reduce ATP2A2 transcription via G-quadruplex formation.
- Downregulation of the mtDNA-inserted ATP2A2 supports the proposed pathophysiological mechanism.

## Abstract

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.