Muscle pathology without severe nerve pathology in a new mouse model of
Charcot-Marie-Tooth disease type 2E.
Authors Shen H, Barry DM, Dale JM, Garcia VB, Calcutt NA, Garcia ML
Submitted By Nigel Calcutt on 1/30/2013
Status Published
Journal Human molecular genetics
Year 2011
Date Published 7/1/2011
Volume : Pages 20 : 2535 - 2548
PubMed Reference 21493625
Abstract 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.

Investigators with authorship
Nigel CalcuttUniversity of California San Diego