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Hum Mol Genet. 2019 Jun 1;28(11):1782-1800. doi: 10.1093/hmg/ddz008.

MFN2 mutations in Charcot-Marie-Tooth disease alter mitochondria-associated ER membrane function but do not impair bioenergetics.

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Department of Neurology, Columbia University Medical Center, New York, NY, USA.
Department of Biology, University of Padova 35131, Italy.
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
Department of Biomedical Sciences, University of Padova, Italy.
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
Department of Neurology, University of Iowa, Iowa City, IA, USA.
Department of Genetics and Development, Columbia University Medical Center, New York, NY, USA.


Charcot-Marie-Tooth disease (CMT) type 2A is a form of peripheral neuropathy, due almost exclusively to dominant mutations in the nuclear gene encoding the mitochondrial protein mitofusin-2 (MFN2). However, there is no understanding of the relationship of clinical phenotype to genotype. MFN2 has two functions: it promotes inter-mitochondrial fusion and mediates endoplasmic reticulum (ER)-mitochondrial tethering at mitochondria-associated ER membranes (MAM). MAM regulates a number of key cellular functions, including lipid and calcium homeostasis, and mitochondrial behavior. To date, no studies have been performed to address whether mutations in MFN2 in CMT2A patient cells affect MAM function, which might provide insight into pathogenesis. Using fibroblasts from three CMT2AMFN2 patients with different mutations in MFN2, we found that some, but not all, examined aspects of ER-mitochondrial connectivity and of MAM function were indeed altered, and correlated with disease severity. Notably, however, respiratory chain function in those cells was unimpaired. Our results suggest that CMT2AMFN2 is a MAM-related disorder but is not a respiratory chain-deficiency disease. The alterations in MAM function described here could also provide insight into the pathogenesis of other forms of CMT.

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