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Abstract

The present invention relates to the engineering an animal model, preferably mammalian models, more preferably a rat model representing Charcot-Marie-Tooth disease 2A (CMT2A) harboring the p.Arg364Trp or p.His361Tyr Mfn2 mutation, whose human counterpart results in a severe, early-onset axonal neuropathy. A model having the p.Arg364Trp Mfn2 mutation is based on a mutation made using zinc finger endonuclease technology in fertilized rat eggs. Cohorts of mutants and wild type littermates were characterized behaviorally and shown to develop multiple motor deficits that worsened over time. Separate cohorts of mutant and wild type rats sacrificed at 7, 40, and 48 weeks and analyzed by light microscopy showed a reduced density of myelinated axons and active axonal degeneration in distal but not proximal nerves, as well as axonal degeneration in the fasciculus gracilis of the cervical spinal cord at 40 and 48 weeks. These findings were not present in the 7-week-old cohort of Mfn2 mutants, or in wild type rats at 7 or 40 weeks. A model having the p.His361Tyr Mfn2 mutation is based on a mutation made using CRISPR/Cas9 gene editing technology. This mutation showed abnormalities in gait dynamics at 8 weeks and a lengthening of the gait cycle at 16 weeks. A genetically authentic animal model for CMT2A developing a progressive axonal neuropathy is a valuable tool for examining the pathogenesis and treatment of CMT2A.

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