The Nefl (E397K) mouse model demonstrates muscle pathology and motor function deficits consistent with CMT2E.

Charcot-Marie-Tooth (CMT) disease affects approximately 1 in 2,500 people and represents a heterogeneous group of inherited peripheral neuropathies characterized by progressive motor and sensory dysfunction. CMT type 2E is a result of mutations in the neurofilament light (NEFL) gene with predominantly autosomal dominant inheritance, often presenting with a progressive neuropathy with distal muscle weakness, sensory loss, gait disturbances, foot deformities, reduced nerve conduction velocity (NCV) without demyelination and typically reduced compound muscle action potential (CMAP) amplitude values. Several Nefl mouse models exist that either alter the mouse Nefl gene or overexpress a mutated human NEFL transgene, each recapitulating various aspects of CMT2E disease. We generated the orthologous NEFL (E396K) mutation in the mouse C57BL/6 background, Nefl (E397K) . In a separate report, we extensively characterized the electrophysiology deficits and axon pathology in Nefl (E397K) mice. In this manuscript, we report our characterization of Nefl (E397K) motor function deficits, muscle pathology and changes in breathing Nefl (+/E397K) and Nefl (E397K/E397K) mice demonstrated progressive motor coordination deficits and muscle weakness through the twelve months of age analyzed, consistent with our electrophysiology findings. Additionally, Nefl (+/E397K) and Nefl (E397K/E397K) mice showed alterations in muscle fiber area, diameter and composition as disease developed. Lastly, Nefl mutant mice showed increased number of apneas under normoxia conditions and increased erratic breathing as well as tidal volume under respiratory challenge conditions. Nefl (E397K/E397K) mice phenotypes and pathology were consistently more severe than Nefl (+/E397K) mice. Collectively, these novel CMT2E models present with a clinically relevant phenotype and make it an ideal model for the evaluation of therapeutics.