Reply: MFN2, a new gene responsible for mitochondrial DNA depletion

Abstract

Sir, we recently showed in Brain that the MFN2 gene, typically responsible for autosomal dominant axonal Charcot–Marie–Tooth disease, is a novel gene associated with ‘mitochondrial DNA breakage’ syndrome (Rouzier et al. , 2012). We described a novel MFN2 heterozygous missense mutation in Tunisian patients who presented with optic atrophy beginning in early childhood, axonal neuropathy and mitochondrial myopathy in adult life with accumulation of mitochondrial DNA deletions in muscle. Renaldo et al. (2012) confirm that MFN2 is involved in mitochondrial DNA maintenance disorders. Indeed, they show that this gene is responsible for a severe phenotype in a child who presented a developmental delay with hypotonia and failure to thrive at the age of 6 months. Evolution was marked by the gradual appearance of ataxia, areflexia, abnormal movements and axonal sensorimotor neuropathy. At the age of 9 years, weight, height and head circumference were <3 SD. The child presented a bilateral optic atrophy and was deaf. Brain MRI was normal. A mitochondrial myopathy, with cytochrome c-oxidase negative fibres, was diagnosed on muscle biopsy and a multiple respiratory chain deficiency was found both in muscle and fibroblasts. Furthermore, Renaldo et al. (2012) found mitochondrial DNA depletion in the patient’s muscle with a low amount of mitochondrial DNA (28% of controls). The association of optic atrophy and axonal neuropathy led the authors to analyse the MFN2 gene and to identify a novel missense heterozygous mutation (p.D210Y) that affects the same aspartic acid residue modified in the Tunisian family that we described previously (p.D210V). A defect in the maintenance of mitochondrial genome can lead to a reduction of mitochondrial DNA copy number and/or multiple mitochondrial DNA deletions. In mouse models, conditional inactivation of Mfn2 in muscle leads to a mitochondrial myopathy with a severe mitochondrial DNA depletion above …