Publication in detail

J Peripher Nerv Syst. 2014 May 23. doi: 10.1111/jns5.12066.

Characterization of the Mitofusin 2 R94W Mutation in a Knock-in Mouse Model.

Strickland, AV; Rebelo, AP; Zhang, F; Price, J; Bolon, B; Silva, JP; Wen, R; Züchner, S

Department of Human Genetics and Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL.

Charcot-Marie-Tooth disease (CMT) comprises a group of heterogeneous peripheral axonopathies affecting 1 in 2,500 individuals. While mutations in several genes cause axonal degeneration in CMT type 2, mutations in mitofusin 2 (MFN2) account for ~90% of the most severe cases, making it the most common cause of inherited peripheral axonal degeneration. MFN2 is an integral mitochondrial outer membrane protein that plays a major role in mitochondrial fusion and motility; yet the mechanism by which dominant mutations in this protein lead to neurodegeneration is still not fully understood. Furthermore, future pre-clinical drug trials will be in need of validated rodent models. We have generated a Mfn2 knock-in mouse model expressing Mfn2R94W , which was originally identified in CMT patients. We have performed behavioral, morphological, and biochemical studies to investigate the consequences of this mutation. Homozygous inheritance leads to premature death at P1, as well as mitochondrial dysfunction, including increased mitochondrial fragmentation in mouse embryonic fibroblasts and decreased ATP levels in newborn brains. Mfn2R94W heterozygous mice show histopathology and age-dependent open field test abnormalities, which support a mild peripheral neuropathy. Although behavior does not mimic the severity of the human disease phenotype, this mouse can provide tissues useful for studying molecular pathways associated with MFN2 point mutations.

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