Characterization of the neflE397K mouse model for Charcot-Marie-Tooth type 2E (CMT2E) therapeutic development


Translational Research

Poster Number: 303


Dennis Perez-Lopez, University of Missouri-Columbia, Sara M. Ricardez Herandez, University of Missouri-Columbia, Mohammed T. Abu-Salah, University of Missouri-Columbia, Tamara Ford, University of Missouri-Columbia, Monique A. Lorson, PhD, University of Missouri, Columbia, Christian L. Lorson, PhD, University of Missouri, Columbia

Charcot-Marie-Tooth (CMT) is the most common hereditary peripheral neuropathy with an incidence of 1:2,500. CMT2 is a type of CMT that presents as a slow, progressive disorder associated with axonal dysfunction. CMT2 clinical symptoms include distal muscle weakness and atrophy, sensory loss, decreased deep-tendon reflexes, toe and foot deformities, and reduced nerve conduction velocity. CMT2E is a type of CMT2 associated with mutations in the gene neurofilament light chain (NEFL). The protein, NF-L, is one of five subunits that makes up neurofilaments and contributes to the axonal cytoskeleton. CMT2E is typically inherited in an autosomal dominant manner with variable onset and severity. To date, no effective therapeutics have been approved for CMT2E. To advance the development of therapeutics and to better understand the underlying biology of disease development, we generated NEFL+/E397K and NEFLE397K/E397K mice. An orthologous mutation was created in the mouse nefl gene that corresponds to human NEFLE397K. We examined the disease-associated allele as a heterozygous and homozygous state to determine if there were any differences in disease severity and pathology. We found in all assays E397K/E397K mice were more severe than +/E397K mice. In both mutants, motor function was impacted, showing gait and balance abnormalities and electrophysiology studies supported our motor function assessments. We are currently examining disease progression and pathology and plan to use this mouse model in the development of therapeutics.