Ighmbp2 mutations and disease pathology: Defining differences that differentiate SMARD1 and CMT2S.

Mutations in the Immunoglobulin mu DNA binding protein 2 (IGHMBP2) gene result in two distinct diseases, SMA with Respiratory Distress Type I (SMARD1) and Charcot Marie Tooth Type 2S (CMT2S). To understand the phenotypic and molecular differences between SMARD1 and CMT2S, and the role of IGHMBP2 in disease development, we generated mouse models based on six IGHMBP2 patient mutations. Previously, we reported the development and characterization of Ighmbp2(D564N/D564N) mice and in this manuscript, we examine two mutations: D565N (D564N in mice) and H924Y (H922Y in mice) in the Ighmbp2(H922Y/H922Y) and Ighmbp2(D564N/H922Y) contexts. We found significant differences between these mouse models, providing critical insight into the role of IGHMBP2 in the pathogenesis of SMARD1 and CMT2S. Importantly, these studies also demonstrate how disease pathogenesis is significantly altered in the context of Ighmbp2 D564N and H922Y homozygous recessive and compound heterozygous mutations. Notably, there were short-lived and long-lived lifespan cohorts within Ighmbp2(D564N/H922Y) mice with early (P12/P16) respiratory pathology serving as a key predictor of lifespan. Despite differences in lifespan, motor function deficits initiated early and progressively worsened in all Ighmbp2(D564N/H922Y) mice. There was decreased limb skeletal muscle fiber area and increased neuromuscular junction (NMJ) denervation in Ighmbp2(D564N/H922Y) mice. Consistent with CMT2S, Ighmbp2(H922Y/H922Y) mice did not have altered lifespans nor respiratory pathology. Interestingly, Ighmbp2(H922Y/H922Y) limb muscle fibers demonstrated an increase in muscle fiber area followed by a reduction while changes in NMJ innervation were minimal even at P180. This is the first study that demonstrates differences associated with IGHMBP2 function within respiration with those within limb motor function. Significant to our understanding of IGHMBP2 function, we demonstrate that there is a direct correlation between disease pathogenesis associated with these IGHMBP2 patient mutations and IGHMBP2 biochemical activity. Importantly, these studies reveal the dynamic differences that are presented when either a single mutant protein is present (IGHMBP2-D564N or IGHMBP2-H922Y) or two mutant proteins are present (IGHMBP2-D564N and IGHMBP2-H922Y) within cells.