SUMMARY:
This study uncovers the mechanistic impact of two human CNTNAP1 mutations in a mouse model and provides proof of concept for gene therapy for CNTNAP1 patients.
TITLE:
Mouse models of human CNTNAP1-associated congenital hypomyelinating neuropathy and genetic restoration of murine neurological deficits
DESCRIPTION:
The Contactin-associated protein 1 (Cntnap1) mouse mutants fail to establish proper axonal domains in myelinated axons. Human CNTNAP1 mutations are linked to hypomyelinating neuropathy-3, which causes severe neurological deficits. To understand the human neuropathology and to model human CNTNAP1^(C323R) and CNTNAP1^(R764C) mutations, we generated Cntnap1^(C324R) and Cntnap1^(R765C) mouse mutants, respectively. Both Cntnap1 mutants show weight loss, reduced nerve conduction, and progressive motor…
CONTENT:
Cell Rep. 2023 Oct 31;42(10):113274. doi: 10.1016/j.celrep.2023.113274. Epub 2023 Oct 19.
ABSTRACT
The Contactin-associated protein 1 (Cntnap1) mouse mutants fail to establish proper axonal domains in myelinated axons. Human CNTNAP1 mutations are linked to hypomyelinating neuropathy-3, which causes severe neurological deficits. To understand the human neuropathology and to model human CNTNAP1C323R and CNTNAP1R764C mutations, we generated Cntnap1C324R and Cntnap1R765C mouse mutants, respectively. Both Cntnap1 mutants show weight loss, reduced nerve conduction, and progressive motor dysfunction. The paranodal ultrastructure shows everted myelin loops and the absence of axo-glial junctions. Biochemical analysis reveals that these Cntnap1 mutant proteins are nearly undetectable in the paranodes, have reduced surface expression and stability, and are retained in the neuronal soma. Postnatal transgenic expression of Cntnap1 in the mutant backgrounds rescues the phenotypes and restores the organization of axonal domains with improved motor function. This study uncovers the mechanistic impact of two human CNTNAP1 mutations in a mouse model and provides proof of concept for gene therapy for CNTNAP1 patients.
PMID:37862170 | DOI:10.1016/j.celrep.2023.113274
SOURCE:
Cell reports
TAGS:
CNTNAP1
CATEGORY:
Research
SUBCATEGORY:
n/a
DATE – PUBLISHED:
2023-10-19T16:14:35Z
DATE – DOI: 2023-10-19T16:14:35Z
DATE – PUBMED: 2023 Oct 31
DATE OUTPUT MATCHED: True
DATE – ADDED:
Fri, 20 Oct 2023 06:00:00 -0400
DATE – RETRIEVED:
11/06/23 06:40AM
2023-11-06T06:40:04-05:00
FEATURED IMAGE:
Media Uploaded (image/jpeg)
IDENTIFIER:
pmid:37862170,doi:10.1016/j.celrep.2023.113274
PUBMED ID:
pubmed:37862170
DOI:
10.1016/j.celrep.2023.113274
LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/37862170/
LINK – DOI:
https://doi.org/10.1016/j.celrep.2023.113274
LINK – PUBLISHER:
https://linkinghub.elsevier.com/retrieve/pii/S221112472301286X
REFERENCES:
CMT Treatment Report, Urgent Research, 2023-11-06T06:40:04-05:00, https://www.cmttreatmentreport.com.