SUMMARY:
These mice will complement existing Ighmbp2 alleles modeling SMARD1 to help understand the complex phenotypic and genotypic heterogeneity that is observed in patients with IGHMBP2 variants.
TITLE:
Clinically relevant mouse models of Charcot-Marie-Tooth Type 2S
DESCRIPTION:
Charcot-Marie-Tooth disease is an inherited peripheral neuropathy that is clinically and genetically heterogenous. Mutations in IGHMBP2, a ubiquitously expressed DNA/RNA helicase, have been shown to cause the infantile motor neuron disease spinal muscular atrophy with respiratory distress type 1 (SMARD1), and, more recently, juvenile-onset Charcot-Marie-Tooth disease Type 2S (CMT2S). Using CRISPR-cas9 mutagenesis we developed the first mouse models of CMT2S (p.Glu365del (E365del) and p.Tyr918Cys…
CONTENT:
Hum Mol Genet. 2022 Nov 22:ddac283. doi: 10.1093/hmg/ddac283. Online ahead of print.
ABSTRACT
Charcot-Marie-Tooth disease is an inherited peripheral neuropathy that is clinically and genetically heterogenous. Mutations in IGHMBP2, a ubiquitously expressed DNA/RNA helicase, have been shown to cause the infantile motor neuron disease spinal muscular atrophy with respiratory distress type 1 (SMARD1), and, more recently, juvenile-onset Charcot-Marie-Tooth disease Type 2S (CMT2S). Using CRISPR-cas9 mutagenesis we developed the first mouse models of CMT2S (p.Glu365del (E365del) and p.Tyr918Cys (Y918C)). E365del is the first CMT2S mouse model to be discovered and Y918C is the first human CMT2S allele knock-in model. Phenotypic characterization of the homozygous models found progressive peripheral motor and sensory axonal degeneration. Neuromuscular and locomotor assays indicate that both E365del and Y918C mice have motor deficits, while neurobehavioral characterization of sensory function found that E365del mutants have mechanical allodynia. Analysis of femoral motor and sensory nerves identified axonal degeneration, which does not impact nerve conduction velocities in E365del mice, but does in the Y918C model. Based on these results, the E365del mutant mouse, as well as the human allele knock-in, Y918C, represent mouse models with the hallmark phenotypes of CMT2S, which will be critical for understanding the pathogenic mechanisms of IGHMBP2. These mice will complement existing Ighmbp2 alleles modeling SMARD1 to help understand the complex phenotypic and genotypic heterogeneity that is observed in patients with IGHMBP2 variants.
PMID:36413117 | DOI:10.1093/hmg/ddac283
SOURCE:
Human molecular genetics
TAGS:
SMARD1
CATEGORY:
Research
SUBCATEGORY:
n/a
DATE – PUBLISHED:
2022-11-22T14:51:18Z
DATE – DOI: 2022-11-22T14:51:18Z
DATE – PUBMED: 2022 Nov 22
DATE OUTPUT MATCHED: True
DATE – ADDED:
Tue, 22 Nov 2022 06:00:00 -0500
DATE – RETRIEVED:
11/22/22 12:38PM
2022-11-22T12:38:15-05:00
FEATURED IMAGE:
Media Uploaded (image/png)
IDENTIFIER:
pmid:36413117,doi:10.1093/hmg/ddac283
PUBMED ID:
pubmed:36413117
DOI:
10.1093/hmg/ddac283
LINK – PUBMED:
https://pubmed.ncbi.nlm.nih.gov/36413117/
LINK – DOI:
https://doi.org/10.1093/hmg/ddac283
LINK – PUBLISHER:
https://academic.oup.com/hmg/advance-article/doi/10.1093/hmg/ddac283/6839995
REFERENCES:
CMT Treatment Report, Urgent Research, 2022-11-22T12:38:15-05:00, https://www.cmttreatmentreport.com.
