Characterization of a Novel Mitofusin 2 Knock-In Mouse Model (P05.061)

OBJECTIVE: To create a functional mouse model in order to investigate the underlying pathophysiology of Charcot-Marie-Tooth disease (CMT) using both molecular and behavioral approaches. BACKGROUND: CMT comprises a group of heterogeneous peripheral axonopathies affecting 1 in 2,500 individuals. While mutations in several genes cause axonal degeneration in CMT, mitofusin 2 (MFN2) variants account for 91% of the most severe cases of the disease; making it the single most important cause of inherited peripheral axonal degeneration. MFN2 is an integral mitochondrial outer membrane protein that plays a major role in mitochondrial fusion and motility, however, the mechanism by which dominant mutations in this protein lead to neurodegeneration is still unknown. DESIGN/METHODS: We have generated a MFN2 knock-in mouse strain containing the R94W mutation originally identified in several CMT families. We have performed behavioral, morphological, cell biological, and biochemical studies to characterize the consequences of this mutation. RESULTS: In mice, homozygous inheritance of this mutation leads to a 10% decrease in birth weight (p 20% decrease in distance traveled and a >30% decrease in vertical movement (p CONCLUSIONS: Although the behavioral heterozygote phenotype is mild, it mimics the human phenotype, with late onset movement deficits, which we are currently trying to enhance using the chemotherapeutic agent vincristine, known to trigger the disease in otherwise asymptomatic patients. Our results thusfar indicate both behavioral and molecular mitochondrial abnormalities, including DNA, ATP, and fusion deficiencies, in MFN2-R94W mice. This model could become a useful tool in future preclinical trials. Supported by: Charcot-Marie-Tooth disease Association and the National Institute of Neurological Disorders and Stroke (NINDS) grants to S.Z.: 5U54NS065712, 5R01NS052767. Disclosure: Dr. Strickland has nothing to disclose. Dr. Rebelo has nothing to disclose. Dr. Zhang has nothing to disclose. Dr. Price has nothing to disclose. Dr. Silva has nothing to disclose. Dr. Wen has nothing to disclose. Dr. Bolon has nothing to disclose. Dr. Zuchner has received (royalty or license fee or contractual rights) payments from Athena Diagnostics.