RESUMEN
Charcot-Marie-Tooth disease (CMT) is the most commonly inherited neurological disorder with a prevalence of 1 in 2500 people worldwide. Patients suffer from degeneration of the peripheral nerves that control sensory information of the foot/leg and hand/arm. Multiple mutations in the neurofilament light polypeptide gene, NEFL, cause CMT2E. Previous studies in transfected cells showed that expression of disease-associated neurofilament light chain variants results in abnormal intermediate filament networks associated with defects in axonal transport. We have now generated knock-in mice with two different point mutations in Nefl: P8R that has been reported in multiple families with variable age of onset and N98S that has been described as an early-onset, sporadic mutation in multiple individuals. Nefl(P8R/+) and Nefl(P8R/P8R) mice were indistinguishable from Nefl(+/+) in terms of behavioral phenotype. In contrast, Nefl(N98S/+) mice had a noticeable tremor, and most animals showed a hindlimb clasping phenotype. Immunohistochemical analysis revealed multiple inclusions in the cell bodies and proximal axons of spinal cord neurons, disorganized processes in the cerebellum and abnormal processes in the cerebral cortex and pons. Abnormal processes were observed as early as post-natal day 7. Electron microscopic analysis of sciatic nerves showed a reduction in the number of neurofilaments, an increase in the number of microtubules and a decrease in the axonal diameters. The Nefl(N98S/+) mice provide an excellent model to study the pathogenesis of CMT2E and should prove useful for testing potential therapies.
