Date of Award

8-2014

Level of Access

Campus-Only Thesis

Degree Name

Master of Science (MS)

Department

Biochemistry

Advisor

Gregory A. Cox

Second Committee Member

Steve Murray

Third Committee Member

Clarissa Henry

Abstract

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an autosomal recessive and devastating neurodegenerative motor neuron disease manifesting in early infancy. The presenting symptom is diaphragmatic paralysis, which necessitates the need for ventillatory support. In addition, SMARD1 patients exhibit distal muscle weakness secondary to motor neuron cell death, which travels proximally as the disease progresses. The gene responsible for this disease has been recently identified as immunoglobulin mu binding protein 2 (Ighmbp2) located on human chromosome 11. In addition, several causative mutations have been identified in SMARD1 patients, including missense, nonsense, splice donor, frameshift mutations, and inframe deletions. 1GHMBP2 is a ubiquitously expressed protein of unknown function with a putative role in the translational machinery of cells. A mouse model for this disease arose spontaneously at the Jackson Laboratory containing a favorable splice donor mutation in intron 4 of the mouse Ighmbp2 gene on chromosome 19. The neuromuscular degeneration mouse, nmd, develops a progressive autosomal recessive neuromuscular disease mimicking the human disease SMARD1 with the exception of diaphragmatic paralysis. While mapping the causative mutation for the nmd mouse, a modifier region from the CAST/EiJ (CAST) inbred strain of mice was discovered that attenuates the severity of the nmd phenotype. A congenic B6.CAST line of mice was engineered, homozygous for C57BL/6J in all regions with the exception of the CAST modifier region on mouse chromosome 13. However, the gene responsible for the modifier effect has not been discovered. Recently, there has been a tremendous advancement in the understanding of neurodegenerative disease. Recent advancements using embryonic and pluripotent stem cell-derived motor neurons as novel tools, have helped to improve our understanding of the mechanisms of neurodegenerative diseases. In this study, we focus on generating and characterizing a mouse embryonic stem cell-derived motor neuron system, encompassing mutant and modifier genotypes, to better understand SMARD1.

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