Knock-in mouse models for CMTX1 show a loss of function phenotype in the peripheral nervous system

Charles K Abrams; Eunjoo Lancaster; Jian J Li; Gabriel Dungan; David Gong; Steven S Scherer; Mona M Freidin

doi:10.1016/j.expneurol.2022.114277

Knock-in mouse models for CMTX1 show a loss of function phenotype in the peripheral nervous system

Exp Neurol. 2023 Feb:360:114277. doi: 10.1016/j.expneurol.2022.114277. Epub 2022 Nov 18.

Authors

Charles K Abrams¹, Eunjoo Lancaster², Jian J Li³, Gabriel Dungan⁴, David Gong⁵, Steven S Scherer⁶, Mona M Freidin⁷

Affiliations

¹ Department of Neurology and Rehabilitation, College of Medicine, University of Illinois at Chicago, 912 South Wood Street, Chicago, IL 60657, USA; Richard and Loan Hill Department of Biomedical Engineering, University of Illinois at Chicago, USA. Electronic address: cabrams1@uic.edu.
² Department of Neurology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.. Electronic address: eoh@pennmedicine.upenn.edu.
³ Department of Neurology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.. Electronic address: LiJian@pennmedicine.upenn.edu.
⁴ Department of Neurology and Rehabilitation, College of Medicine, University of Illinois at Chicago, 912 South Wood Street, Chicago, IL 60657, USA.
⁵ Richard and Loan Hill Department of Biomedical Engineering, University of Illinois at Chicago, USA. Electronic address: gong9@uic.edu.
⁶ Department of Neurology, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.. Electronic address: sscherer@pennmedicine.upenn.edu.
⁷ Department of Neurology and Rehabilitation, College of Medicine, University of Illinois at Chicago, 912 South Wood Street, Chicago, IL 60657, USA. Electronic address: mfreidin@uic.edu.

PMID: 36403785
DOI: 10.1016/j.expneurol.2022.114277

Abstract

The X-linked form of Charcot-Marie-Tooth disease (CMTX1) is the second most common form of CMT. In this study we used CRISPR/Cas9 to develop new "knock-in" models of CMTX1 that are more representative of the spectrum of mutations seen with CMTX1 than the Cx32 knockout (KO) mouse model used previously. We compared mice of four genotypes - wild-type, Cx32KO, p.T55I, and p.R75W. Sciatic motor conduction velocity slowing was the most robust electrophysiologic indicator of neuropathy, showing reductions in the Cx32KO by 3 months and in the p.T55I and p.R75W mice by 6 months. At both 6 and 12 months, all three mutant genotypes showed reduced four limb and hind limb grip strength compared to WT mice. Performance on 6 and 12 mm width balance beams revealed deficits that were most pronounced at on the 6 mm balance beam at 6 months of age. There were pathological changes of myelinated axons in the femoral motor nerve in all three mutant lines by 3 months of age, and these became more pronounced at 6 and 12 months of age; sensory nerves (femoral sensory and the caudal nerve of the tail) appeared normal at all ages examined. Our results demonstrate that mice can be used to show the pathogenicity of human GJB1 mutations, and these new models for CMTX1 should facilitate the preclinical work for developing treatments for CMTX1.

Keywords: CMT; Charcot-Marie-Tooth disease; Connexin; GJB1; Gap junction; Inherited peripheral nerve disease; Mouse models.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Charcot-Marie-Tooth Disease* / genetics
Charcot-Marie-Tooth Disease* / pathology
Connexins / genetics
Disease Models, Animal
Gap Junction beta-1 Protein
Mice
Mice, Knockout
Mutation / genetics
Peripheral Nervous System* / pathology
Phenotype

Substances

Connexins

Supplementary concepts

Charcot-Marie-Tooth disease, X-linked, 1