The MFN2 gene is responsible for mitochondrial DNA instability and optic atrophy 'plus' phenotype

TLDR

MFN2 and OPA1 encode dynamin‑like GTPases that mediate mitochondrial fusion and are linked to Charcot‑Marie‑Tooth type 2A and autosomal dominant optic atrophy, respectively. The study reports a large family with early‑onset optic atrophy, axonal neuropathy, and adult‑onset mitochondrial myopathy. A novel MFN2 missense mutation (c.629A>T, p.D210V) causes an optic‑atrophy‑plus phenotype with multiple mtDNA deletions, respiratory chain deficiency, fragmented mitochondria, reduced MFN2 protein, and impaired repair of stress‑induced mtDNA damage, indicating that MFN2‑mediated fusion is essential for mtDNA stability.

Abstract

MFN2 and OPA1 genes encode two dynamin-like GTPase proteins involved in the fusion of the mitochondrial membrane. They have been associated with Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy, respectively. We report a large family with optic atrophy beginning in early childhood, associated with axonal neuropathy and mitochondrial myopathy in adult life. The clinical presentation looks like the autosomal dominant optic atrophy 'plus' phenotype linked to OPA1 mutations but is associated with a novel MFN2 missense mutation (c.629A>T, p.D210V). Multiple mitochondrial DNA deletions were found in skeletal muscle and this observation makes MFN2 a novel gene associated with 'mitochondrial DNA breakage' syndrome. Contrary to previous studies in patients with Charcot-Marie-Tooth disease type 2A, fibroblasts carrying the MFN2 mutation present with a respiratory chain deficiency, a fragmentation of the mitochondrial network and a significant reduction of MFN2 protein expression. Furthermore, we show for the first time that impaired mitochondrial fusion is responsible for a deficiency to repair stress-induced mitochondrial DNA damage. It is likely that defect in mitochondrial DNA repair is due to variability in repair protein content across the mitochondrial population and is at least partially responsible for mitochondrial DNA instability.