Investigating how Ighmbp2 mutations alter disease progression in mouse models of SMARD1 and CMT2S
Board Location: #95
Discipline: Neuroscience
Subcategory: Biochemistry (not Cell and Molecular Biology and Genetics)
Session: 3
Bassil Ahmed - University of Missouri
Co-Author(s): Sara M. Ricardez Hernandez1, University of Missouri, Yaser Al Rawi1, University of Missouri, Monique A. Lorson1,2, University of Missouri, Christian L. Lorson1,2, University of Missouri,
IGHMBP2 (Immunoglobulin Mu DNA Binding Protein 2) is a DNA/RNA helicase with proposed roles in many processes including ribosome biogenesis and translation. None of these proposed IGHMBP2 roles have been linked to disease.However, mutations in the IGHMBP2 gene result in two distinct diseases: SMARD1 (Spinal Muscular Atrophy with Respiratory Distress Type 1) and CMT2S (Charcot Marie Tooth Disease 2S). The primary clinical symptom of SMARD1 is respiratory distress. SMARD1 patients present with progressive motor neuron degeneration, muscle atrophy and weakness among other clinical findings. SMARD1 patients experience a decrease in lifespan without respiratory intervention. CMT2S presents with progressive muscle atrophy and weakness, sensory loss, walking difficulties, and hand and feet deformities. There are no respiratory complications nor a decrease in lifespan in CMT2S patients. The type of mutation that defines each disease is not clearly understood nor what determines the disease severity. We have generated mouse models based on patient mutations to understand the role of IGHMBP2 within cellular processes and to examine how different mutations alter disease. These studies focus on two of the mutations, Ighmbp2-D564N (D565N in humans) and Ighmbp2-H922Y (H924Y in humans) in the homozygous recessive and compound heterozygous contexts. These studies examine lifespan, motor function, neuromuscular junction and muscle pathology, respiration, and electrophysiology to understand the relationship of genotype to phenotype. Our objective is to increase our understanding of IGHMBP2 function, pathways, and the impact of disease-causing mutations on disease development, in order to shift disease severity and alleviate clinical symptoms.
Funder Acknowledgement(s): BDA is support National Institute of General Medical Sciences (NIGMS) grant T34 GM 136493These studies are supported by NIH/NINDS R01NS113765 to MAL and CLL SMRH is supported by the HHMI Gilliam Fellowship
Faculty Advisor: Monique Lorson, lorsonm@missouri.edu
Role: Within this project I have conducted muscle tissue dissections, muscle fiber staining, neuromuscular junction staining, and end plate staining, perfusions, tissue dissections, staining of tissue and data analyses as well as assisting with conducting motor function assessments, plethysmography, and electrophysiology