title: Severity of Demyelinating and Axonal Neuropathy Mouse Models Is Modified by Genes Affecting Structure and Function of Peripheral Nodes.
abstract: 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.
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA; Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME 04469, USA.
authors.forename: Kathryn H
authors.initials: KH
authors.lastname: Morelli
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Seburn
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: David G
authors.initials: DG
authors.lastname: Schroeder
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA; Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME 04469, USA.
authors.forename: Emily L
authors.initials: EL
authors.lastname: Spaulding
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Loiuse A
authors.initials: LA
authors.lastname: Dionne
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA; Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME 04469, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Cox
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA; Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME 04469, USA. Electronic address: robert.burgess@jax.org.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Burgess
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics* / Q000473:pathology; D003711:Demyelinating Diseases / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D006579:Heterozygote; D047908:Intracellular Signaling Peptides and Proteins; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D062557:NAV1.6 Voltage-Gated Sodium Channel / Q000235:genetics; D009469:Neuromuscular Junction / Q000378:metabolism; D010525:Peripheral Nerves / Q000473:pathology*
chemical_list: D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; D047908:Intracellular Signaling Peptides and Proteins; D062557:NAV1.6 Voltage-Gated Sodium Channel; C491151:Nrcam protein, mouse; C491046:Scn8a protein, mouse; C552538:Sh3tc2 protein, mouse
keywords: Charcot-Marie-Tooth disease; axons; degeneration; genetic modifiers; hereditary sensory; length constant; motor neuropathy