MFN2 mutations cause compensatory mitochondrial DNA proliferation

ARTICLESir, We read with great interest the report of a Tunisian family by Rouzier et al . (2011) describing the neurological disorder linked to a novel heterozygous missense mutation in MFN2 (1p36.2) (Rouzier et al ., 2011). MFN2 mutations typically cause autosomal dominant axonal Charcot–Marie–Tooth disease (CMT2A, OMIM 609260), with peripheral nerve degeneration occasionally associated with visual failure and optic atrophy (Zuchner et al ., 2004, 2006). Interestingly, the clinical manifestations among mutational carriers in this Tunisian family were even more variable, ranging from asymptomatic subclinical disease to an axonal sensorimotor neuropathy complicated by optic atrophy, deafness, cerebellar ataxia and proximal myopathy. Furthermore, the intriguing finding of cytochrome c oxidase (COX)-deficient fibres and multiple mitochondrial DNA deletions in skeletal muscle biopsies suggest that MFN2 mutations can result in disturbed mitochondrial DNA maintenance and an overt respiratory chain defect, in addition to marked fragmentation of the mitochondrial network. These deleterious consequences are strikingly reminiscent of the pathological features recently highlighted in Brain for autosomal dominant optic atrophy due to OPA1 mutations (Amati-Bonneau et al ., 2008; Hudson et al ., 2008; Yu-Wai-Man et al ., 2010 a ). Here, we provide additional evidence that MFN2 …