SUMMARY:
Mice can be used to show the pathogenicity of human GJB1 mutations.
TITLE:
Knock-in mouse models for CMTX1 show a loss of function phenotype in the peripheral nervous system
DESCRIPTION:
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…
CONTENT:
Exp Neurol. 2022 Nov 17:114277. doi: 10.1016/j.expneurol.2022.114277. Online ahead of print.
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 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.
PMID:36403785 | DOI:10.1016/j.expneurol.2022.114277
SOURCE:
Experimental neurology
TAGS:
Mice
CATEGORY:
Research
SUBCATEGORY:
n/a
DATE – PUBLISHED:
2022-11-18T14:07:34Z
DATE – DOI: 2022-11-18T14:07:34Z
DATE – PUBMED: 2022 Nov 17
DATE OUTPUT MATCHED: True
DATE – ADDED:
Sun, 20 Nov 2022 06:00:00 -0500
DATE – RETRIEVED:
11/21/22 01:00AM
2022-11-21T01:00:16-05:00
FEATURED IMAGE:
Media Uploaded (image/png)
IDENTIFIER:
pmid:36403785,doi:10.1016/j.expneurol.2022.114277
PUBMED ID:
pubmed:36403785
DOI:
10.1016/j.expneurol.2022.114277
LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36403785/
LINK – DOI:
https://doi.org/10.1016/j.expneurol.2022.114277
LINK – PUBLISHER:
https://linkinghub.elsevier.com/retrieve/pii/S0014488622003028
REFERENCES:
CMT Treatment Report, Urgent Research, 2022-11-21T01:00:16-05:00, https://www.cmttreatmentreport.com.
