Mutation of OPA1 causes dominant optic atrophy with external ophthalmoplegia, ataxia, deafness and multiple mitochondrial DNA deletions: a novel disorder of mtDNA maintenance

TLDR

Mutations in nuclear genes that maintain mitochondrial DNA cause a spectrum of clinical phenotypes characterized by secondary accumulation of multiple mtDNA deletions, and most autosomal‑dominant progressive external ophthalmoplegia families carry mutations in polγ, Twinkle, or Ant1. A heterozygous missense mutation in OPA1 produces multiple mtDNA deletions and cytochrome‑c oxidase mosaicism in skeletal muscle, leading to childhood optic atrophy followed by progressive external ophthalmoplegia, ataxia, deafness, and sensory‑motor neuropathy, thereby establishing OPA1 as essential for mtDNA maintenance and linking it to disorders with secondary mtDNA defects.

Abstract

Mutations in nuclear genes involved in mitochondrial DNA (mtDNA) maintenance cause a wide range of clinical phenotypes associated with the secondary accumulation of multiple mtDNA deletions in affected tissues. The majority of families with autosomal dominant progressive external ophthalmoplegia (PEO) harbour mutations in genes encoding one of three well-characterized proteins—polγ, Twinkle or Ant 1. Here we show that a heterozygous mis-sense mutation in OPA1 leads to multiple mtDNA deletions in skeletal muscle and a mosaic defect of cytochrome c oxidase (COX). The disorder presented with visual failure and optic atrophy in childhood, followed by PEO, ataxia, deafness and a sensory-motor neuropathy in adult life. COX-deficient skeletal muscle fibres contained supra-threshold levels of multiple mtDNA deletions, and genetic linkage, sequencing and expression analysis excluded POLG1, PEO1 and SLC25A4, the gene encoding Ant 1, as the cause. This demonstrates the importance of OPA1 in mtDNA maintenance, and implicates OPA1 in diseases associated with secondary defects of mtDNA.