Clinically relevant mouse models of severe spinal muscular atrophy with respiratory distress type 1.
Document Type
Article
Publication Date
10-7-2024
Original Citation
Holbrook S,
Hicks A,
Martin P,
Hines T,
Castro H,
Cox GA.
Clinically relevant mouse models of severe spinal muscular atrophy with respiratory distress type 1. Hum Mol Genet. 2024;33(20):1800-14.
Keywords
JMG, Animals, Mice, Disease Models, Animal, Muscular Atrophy, Spinal, DNA-Binding Proteins, Humans, Respiratory Distress Syndrome, Newborn, Transcription Factors, Alleles, Mutation, CRISPR-Cas Systems, Gene Editing, Motor Neurons, Phenotype
JAX Source
Hum Mol Genet. 2024;33(20):1800-14.
ISSN
1460-2083
PMID
39128026
DOI
https://doi.org/10.1093/hmg/ddae116
Grant
This work was supported by National Institutes of Health [R01 NS102414 to G.A.C.]; and the Sims Family Fund [to G.A.C.].
Abstract
Spinal Muscular Atrophy with Respiratory Distress (SMARD1) is a lethal infantile disease, characterized by the loss of motor neurons leading to muscular atrophy, diaphragmatic paralysis, and weakness in the trunk and limbs. Mutations in IGHMBP2, a ubiquitously expressed DNA/RNA helicase, have been shown to cause a wide spectrum of motor neuron disease. Though mutations in IGHMBP2 are mostly associated with SMARD1, milder alleles cause the axonal neuropathy, Charcot-Marie-Tooth disease type 2S (CMT2S), and some null alleles are potentially a risk factor for sudden infant death syndrome (SIDS). Variant heterogeneity studied using an allelic series can be informative in order to create a broad spectrum of models that better exhibit the human variation. We previously identified the nmd2J mouse model of SMARD1, as well as two milder CMT2S mouse models. Here, we used CRISPR-Cas9 genome editing to create three new, more severe Ighmbp2 mouse models of SMARD1, including a null allele, a deletion of C495 (C495del) and a deletion of L362 (L362del). Phenotypic characterization of the IGHMBP2L362del homozygous mutants and IGHMBP2C495del homozygous mutants respectively show a more severe disease presentation than the previous nmd2J model. The IGHMBP2L362del mutants lack a clear denervation in the diaphragm while the IGHMBP2C495del mutants display a neurogenic diaphragmatic phenotype as observed in SMARD1 patients. Characterization of the Ighmbp2-null model indicated neo-natal lethality (median lifespan = 0.5 days). These novel strains expand the spectrum of SMARD1 models to better reflect the clinical continuum observed in the human patients with various IGHMBP2 recessive mutations.
Creative Commons License
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