The Ighmbp2D564N mouse model is the first SMARD1 model to demonstrate respiratory defects

Hum Mol Genet. 2022 Apr 22;31(8):1293-1307. doi: 10.1093/hmg/ddab317.

Abstract

Spinal muscular atrophy with respiratory distress type I (SMARD1) is a neurodegenerative disease defined by respiratory distress, muscle atrophy and sensory and autonomic nervous system defects. SMARD1 is a result of mutations within the IGHMBP2 gene. We have generated six Ighmbp2 mouse models based on patient-derived mutations that result in SMARD1 and/or Charcot-Marie Tooth Type 2 (CMT2S). Here we describe the characterization of one of these models, Ighmbp2D564N (human D565N). The Ighmbp2D564N/D564N mouse model mimics important aspects of the SMARD1 disease phenotype, including motor neuron degeneration and muscle atrophy. Ighmbp2D564N/D564N is the first SMARD1 mouse model to demonstrate respiratory defects based on quantified plethysmography analyses. SMARD1 disease phenotypes, including the respiratory defects, are significantly diminished by intracerebroventricular (ICV) injection of ssAAV9-IGHMBP2 and the extent of phenotypic restoration is dose-dependent. Collectively, this model provides important biological insight into SMARD1 disease development.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • DNA-Binding Proteins / genetics
  • Disease Models, Animal
  • Humans
  • Mice
  • Muscular Atrophy
  • Muscular Atrophy, Spinal* / genetics
  • Mutation
  • Neurodegenerative Diseases*
  • Respiratory Distress Syndrome, Newborn
  • Transcription Factors / genetics

Substances

  • DNA-Binding Proteins
  • IGHMBP2 protein, human
  • Ighmbp2 protein, mouse
  • Transcription Factors

Supplementary concepts

  • Spinal muscular atrophy with respiratory distress 1