Room: Exhibit Hall
Yaser Al Rawi - University of Missouri
Co-Author(s): Sara M. Ricardez Hernandez, University of Missouri, Columbia, MO; Monique A. Lorson, University of Missouri, Columbia, MO; Christian L. Lorson, University of Missouri, Columbia, MO
Charcot-Marie-Tooth Disease type 2S (CMT2S) and Spinal Muscular Atrophy with respiratory distress type 1 (SMARD1) are two rare neurodegenerative diseases that arise from mutations in the Immunoglobulin- μ-Binding Protein 2 (IGHMBP2) gene. SMARD1 manifests early in life with respiratory distress as the primary clinical symptom and distal to proximal spread of muscle atrophy. SMARD1 clinical symptoms include: prenatal growth retardation, autonomic defects, contractures and muscle weakness among others. Without mechanical ventilation, patients typically die before 12 months of age. CMT2S clinical symptoms typically begin later without respiratory complication. CMT2S presents as a slow but progressive muscle wasting and weakness in patients, and symptoms include delayed development, sensory loss, and difficulty walking, but typically no reduction in lifespan. IGHMBP2 is an RNA/DNA helicase with many proposed functions including translation and ribosome biogenesis. It is unknown what aspects of IGHMBP2 function result in disease. To understand disease progression and what molecular changes define SMARD1 or CMT2S, we generated six Ighmbp2 mouse models that were based on patient mutations. Two of those mutations, D564N (D565N in humans) and H922Y (H924Y in humans) are the focus of these studies. The D564N mutation is located within the helicase domain, while the H922Y mutation is in the zinc finger domain (ZnF) of IGHMBP2. The previously characterized Ighmbp2D564N/D564N mice show significant reduction in lifespan, respiratory defects, motor function defects, severe muscle denervation and muscle atrophy. Preliminary data show that Ighmbp2H922Y/H922Y mice present with phenotypes consistent with CMT2S (hindlimb weakness, walking and gait deficits) with no decrease in lifespan compared to wildtype mice. As the D564N mouse model presented with severe respiratory deficiencies and phenotypes consistent with SMARD1, we wanted to determine the extent to which the H922Y mutation attenuated any of these phenotypes. Compound heterozygous Ighmbp2D564N/H922Y mice were generated, and fitness assays (lifespan and weight) and motor function assessments were performed. Additionally, respiration was examined by whole-body plethysmography. Here we present our findings and show that the Ighmbp2D564N/H922Y mice show milder respiratory deficiency, increased lifespan, and motor function when compared to Ighmbp2D564N/D564N mice. This mouse model should provide key insights into what changes result in severe respiratory deficiency. We expect that the H922Y mutation leads to CMT2S, and that the results will show the combination of mutations D564N and H922Y leads to milder symptoms in motor deficit. Our future steps are to analyze the cellular pathogenesis of the two models to develop a targeted treatment for SMARD1 and CMT2S.
Funder Acknowledgement(s): YMA is supported by funding from MU’s MARC Fellows Program via grant number T34 GM 136493 from the National Institute of General Medical Science (NIGMS), a component of the National Institutes of Health (NIH).SMRH is supported by the Howard Hughes Medical Institute Gilliam FellowshipCLL and MAL are supported by NIH/NINDS R01NS113765
Faculty Advisor: Christian L. Lorson, email@example.com
Role: I was involved in setting up heterozygous breeders for the creation of our homozygous mutant mice. I have genotyped the neonatal mice to determine which mice are wildtype (controls), H922Y mutants, and heterozygous carriers. I have conducted the behavioral testing, including the plethysmography analysis to assess breathing defects, and Catwalk for gait analysis. I have analyzed the Catwalk data. I will assist in the perfusion of the mice to be later dissected, section the different muscles and performing the immunofluorescence staining. I will analyze the images using different software.