Novel SMARD1 Mouse Models: Characterization and Evaluation of Potential Therapeutic Targets

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Abstract When motor neurons degenerate, they lose their ability to communicate with their downstream muscle targets and, as a result, muscles weaken, often leading to paralysis and death. This commonality is shared between rare diseases such as Spinal Muscular Atrophy, Amyotrophic Lateral Sclerosis, and SMA with Respiratory Distress Type I (SMARD1). Collectively “rare” disorders are strikingly common, afflicting ~30 million people in the United States alone. Understanding commonalties between these different conditions not only leverages disease-specific research but also provides opportunities to exploit shared biochemical pathways for therapeutic development. With this as a backdrop, this project focuses on the IGHMBP2 gene, that when mutated results in a severe motor neuron degenerative disease, SMARD1; mutations in IGHMBP2 are also found in a subset of CMT2 (Charcot-Marie-Tooth Type2) patients. IGHMBP2 is a ubiquitously expressed protein with helicase function and proposed roles in RNA regulation or RNA metabolism. SMARD1 is an autosomal recessive motor neuron disease that primarily affects children, with a life expectancy of ~13 months. The prevalence of SMARD1 is ~1 percent of early onset SMA patients. SMARD1 is initially characterized by distal lower limb muscle atrophy with proximal muscle weakness later. The first major SMARD1 clinical symptom, respiratory complication, is due to diaphragmatic paralysis. We have recently generated four unpublished mouse models with mutations in Ighmbp2 that correlate to mutations within the SMARD1 patient population. The objective of this project is to characterize two of the new models with Ighmbp2 mutations C495X and D564N. C495X correlates to the patient C496X mutation that is the most prevalent IGHMBP2 mutation identified in SMARD1 and is also found in some CMT2 patients. C495X is found as a homozygous recessive mutation and as a compound heterozygous mutation in patients and presents with respiratory distress and motor neuron defects as early as days and as late as years. D564N correlates to the patient D565N mutation and has only been identified as a compound heterozygous mutation with clinical symptoms initiating as early as several months of age. D565N protein binds nucleic acid, has ATPase activity, but lacks helicase activity. Experiments in AIM I are designed to address: disease onset, disease severity, and the relationship between the type of mutation and SMARD1 symptoms. In AIM II we will examine the molecular and cellular phenotypes, including RNA and protein expression, motor neuron and muscle analyses, and respiratory function. These data will be compared to studies that have examined the nmd mouse (the only SMARD1 model currently available) and SMA and ALS models. AIM III will address translational approaches. These studies should provide significant information into the role of Ighmbp2 in cellular processes and SMARD1 development. Additionally, these studies should provide a greater knowledge base to facilitate therapeutic development and a better understanding of the similarities and differences between related neurological diseases to more completely address therapeutic development.