The FVB-nmd SMARD1 mouse presents with early respiratory deficits and pathology that significantly impact lifespan

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare, inherited genetic disease caused by mutations in the immunoglobulin mu binding protein (IGHMBP2) gene that result in spinal muscular atrophy with respiratory distress (SMARD1) or Charcot-Marie-Tooth Type 2S (CMT2S). SMARD1 clinical symptoms include respiratory failure, progressive muscular weakness, feeding deficiencies, and sensory and autonomic defects. In this paper, we examined respiration in the FVB-Ighmbp2nmd/nmd (FVB-nmd) mouse model that has an average lifespan of twenty days. The previously reported B6.BKS Ighmbp2nmd-2J/J (B6-nmd-2 J) mouse model has a variable lifespan ranging from four weeks to seven months with no respiratory distress noted until end stage; therefore, we wanted to determine whether the reduced lifespan of FVB-nmd mice was attributed to respiratory-associated changes. Our findings demonstrate that FVB-nmd mice showed severe respiratory deficiencies in nearly all parameters quantified by plethysmography. Surprisingly, the innervation status of neuromuscular junctions of respiratory and oral muscles were largely unaffected throughout the lifespan of the FVB-nmd mice. Diaphragm muscle fibers were reduced in size and the phrenic nerve demonstrated changes in fiber size and myelination. The hypoglossal nerve innervating the tongue also showed disease pathology. Assessment of lung tissue also revealed significant pathology. The investigation of the FVB-Ighmbp2nmd/nmd mouse model provides insight on how reduced IGHMBP2 protein alters respiratory function and impacts lifespan.