Mutations in the Immunoglobulin-μ-Binding Protein 2 (IGHMBP2) gene give rise to two different diseases, spinal muscular atrophy with respiratory distress type 1 (SMARD1) and Charcot Marie Tooth Type 2S (CMT2S). SMARD1 is an infantile motor neuron disease characterized by distal muscle atrophy and respiratory impairment; without artificial ventilation patients die within the first 13 months of life. CMT2S is an axonal neuropathy that leads to progressive weakness, wasting, and sensory loss. To better understand the impact of different IGHMBP2 mutations on disease severity and progression, we generated six mouse models based on patient mutations. In this study, we focus on the characterization of one of these models, the compound heterozygous Ighmbp2D564N/H922Y mice.
As compound heterozygous IGHMBP2 mutations are prevalent in the patient population, we wanted to investigate the extent to which disease severity and progression were altered in the Ighmbp2D564N/H922Y mouse. Our studies demonstrate that the D564N/H922Y mouse model depicts an intermediate phenotype. Lifespan is expanded, however, reduced weight, severe hindlimb paralysis, and poor motor function performance are still observed. Quantitative whole-body plethysmography analyses performed under normoxia and challenge conditions showed that unlike the Ighmbp2D564N/D564N model, Ighmbp2D564N/H922Y mutant mice did not display severe respiratory distress and were able to respond to respiratory challenge conditions.
Together these results show that the D564N/H922Y compound heterozygous mouse model demonstrates less severe disease phenotypes than the D564N/D564N mouse model. Understanding how different mutations affect disease severity and progression as well as the function of IGHMPB2 will be important in our understanding of these diseases.