Clinically relevant mouse models of Charcot–Marie–Tooth type 2S

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.

Exploring the relationship between IGHMBP2 gene mutations and spinal muscular atrophy with respiratory distress type 1 and Charcot-Marie-Tooth disease type 2S: a systematic review

“…IGHMBP2 gene mutations are associated with two diseases, SMARD1 (Rzepnikowska et al, 2022) and CMT2S (Martin et al, 2022), which exhibit significant differences in phenotype. Therefore, understanding the detection rate of these two diseases is important.…”

Disease Mechanisms and Therapeutic Approaches in SMARD1—Insights from Animal Models and Cell Models

“…Taken together, both models develop a less severe phenotype than the Nmd 2J mouse, but this is similar to CMT2S patients without cardiac phenotypes and shortened lifespans [50]. Currently, the susceptibility to cardiomyopathy in SMARD1 patients is still an open question.…”

“…IGHMBP2 mutations in patients do not only exclusively lead to motoneuron loss; they also lead to peripheral neuropathies for reasons that are still unknown. Martin and colleagues were the first to characterize CMT2S mouse models with mutations in two different regions of the helicase [50] (Table 1). The E356del variant (C57BL/6J-Ighmbp2 em1Cx /Cx) was introduced into the helicase domain via CRISPR/Cas, while the Y918C variant (C57BL/6J-Ighmbp2 em5Cx /Cx), generated by a knock-in technique, was localized to the C-terminus, a domain that regulates RNA-binding affinities.…”

IGHMBP2 deletion suppresses translation and activates the integrated stress response

“…The relative processivity of IGHMBP2 as an RNA helicase is yet to be determined and will be important to clarify especially upon diverse RNA structures. A resolved RNA-bound structure of IGHMBP2 has further evidenced disease mutations disrupt helicase activity (Guenther et al 2009a;Lim et (Banchs et al 2009;Martin et al 2022).…”