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

Publication date: 28 March 2017
Source:Cell Reports, Volume 18, Issue 13
Author(s): Kathryn H. Morelli, Kevin L. Seburn, David G. Schroeder, Emily L. Spaulding, Loiuse A. Dionne, Gregory A. Cox, Robert W. Burgess
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.

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Teaser

Genetic modifiers contribute to the variability of inherited peripheral neuropathies. Morelli et al. report that a mutation subtly impacting peripheral nodes of Ranvier worsens both demyelinating and axonal neuropathy mouse models, at least in part through decreased sodium channel function. Considering such variants may improve prognostic accuracy for these conditions.


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