Mutations in neurofilament light (NF-L) have been linked to
Charcot-Marie-Tooth disease type 2E (
CMT2E) in humans. To provide insight into disease pathogenesis, we developed a novel line of
CMT2E mice that constitutively express human NF-L (hNF-L) with a
glutamic acid to
lysine mutation at position 397 (hNF-L(E397K)). This new line of mice developed signs consistent with
CMT2E patients. Disease signs were first observed at 4 months in hNF-L(E397K) mice, and consisted of aberrant hind limb posture, digit
deformities, reduced voluntary locomotor activity, reduced motor nerve conduction velocities (MNCVs) and
muscle atrophy. Reduced voluntary locomotor activity and muscle pathology occurred without significant
denervation, and hNF-L(E397K) mice showed relatively mild signs of nerve pathology. Nerve pathology in hNF-L(E397K) mice was characterized by ectopic accumulations of phosphorylated NFs in motor neuron cell bodies as early as 1 month. Moreover, NF organization was altered in motor and sensory roots, with small motor axons being most affected. Peak axonal diameter was reduced for small motor axons prior to and after the onset of overt phenotypes, whereas large motor axons were affected only after onset, which correlated with reduced MNCVs. Additionally, there was a small reduction in the number of sensory axons in symptomatic hNF-L(E397K) mice. hNF-L(E397K) mice are a novel line of
CMT2E mice that recapitulate many of the overt phenotypes observed in
CMT2E patients and hNF-L(P22S) mice. The cellular pathology observed in hNF-L(E397K) mice differed from that recently reported in hNF-L(P22S) mice, suggesting that overt
CMT2E phenotypes may arise through different cellular mechanisms.