Severity of Demyelinating and Axonal Neuropathy Mouse Models Is Modified by Genes Affecting Structure and Function of Peripheral Nodes

Abstract

SUMMARY Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited polyneuropathies. Mutations in 80 genetic loci can cause forms of CMT, resulting in demyelination and axonal dysfunction. The clinical presentation, including sensory deficits, distal muscle weakness, and atrophy, can vary greatly in severity and progression. Here, we used mouse models of CMT to demonstrate genetic interactions that result in a more severe neuropathy phenotype. The cell adhesion molecule Nrcam and the Na+ channel Scn8a (NaV1.6) are important components of nodes. Homozygous Nrcam and heterozygous Scn8a mutations synergized with both an Sh3tc2 mutation, modeling recessive demyelinating Charcot-Marie-Tooth type 4C, and mutations in Gars, modeling dominant axonal Charcot-Marie-Tooth type 2D. We conclude that genetic variants perturbing the structure and function of nodes interact with mutations affecting the cable properties of axons by thinning myelin or reducing axon diameter. Therefore, genes integral to peripheral nodes are candidate modifiers of peripheral neuropathy.

Allele-specific RNA interference prevents neuropathy in Charcot-Marie-Tooth disease type 2D mouse models

“…Defects in NMJ innervation were evident at 6 weeks of age, and examples of fully innervated, partially innervated, and denervated junctions are shown in Supplemental Figure 4, C-G, and resemble those in previously reported Gars mice (22,(26)(27)(28). Thus, Gars ΔETAQ/huEx8 mice display primary features of peripheral neuropathy similar to other established mouse models of CMT2D, confirming that the ΔETAQ GARS mutation is pathogenic (22,26,29,30).…”

“…Grip strength was evaluated by wire hang test (20,26) to evaluate gross muscle strength and endurance. Nerve conduction studies, motor nerve histology and analysis, NMJ immunofluorescence and analysis, and body weight evaluation were completed as previously described (20,30). These studies were not formally blinded.…”

DSCAM promotes self-avoidance in the developing mouse retina by masking the functions of cadherin superfamily members

“…S5). We crossed Nrcam null mutant mice (44) to conditional floxed Dscam mutants, with recombination restricted to the retina by Pax6α-Cre (Dscam rko/rko ; rko for retinal knockout), and analyzed DA cell spacing and neurite fasciculation at P14. We did not find any reduction in fasciculation in Dscam rko/rko ;Nrcam −/− mutants compared with Dscam rko/rko mutants alone ( Fig.…”

Impaired Mitochondrial Mobility in Charcot-Marie-Tooth Disease

“…Plays a role in mitotic spindle assembly and metaphase plate congression. (Weedon et al, 2011) GARS1/CMT2D Catalyzes the attachment of glycine to tRNA (Hamaguchi, Ishida, Iwasa, Abe, & Yamada, 2010;James et al, 2006;Morelli et al, 2017;Motley et al, 2011;W. Xie, Schimmel, & Yang, 2006) GDAP1/CMT2K; CMTRIA; CMT4A*…”