Clinical & Molecular Analysis of Neuromuscular Disorders

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DESCRIPTION (provided by applicant): Since the mid1980s, science has made tremendous progress in understanding genetics, including the roles that genes play in certain diseases. In particular, significant strides have been made towards identifying the molecular basis of neuromuscular disorders. These recent findings have initiated exciting studies of genebased therapies. The focus of our laboratory has been on the clinical and molecular pathogenesis of unique neuromuscular diseases of families from Central Illinois. The original K02 grant was for clinical and molecular delineation of a unique combination of features in a large family with CharcotMarieTooth and deafness. This ongoing study has led to the identification of a unique mutation in the PMP22 gene that cosegregates with the disease phenotype. We have recruited additional families to improve our understanding of this interesting phenotype. Molecular studies propose to examine the mechanism of hearing loss by determining patterns of PMP22 expression in the cochlea of mice throughout development and identifying new PMP22 mutations associated with deafness. As a result of our interest in neuromuscular disorders we have expanded our research interests to include another unique disorder: autosomal dominant limbgirdle muscular dystrophy in combination with Paget disease of bone and Alzheimer disease in some individuals. We have mapped this disorder to a unique focus on chromosome 9. The focus of our research is to identify the gene that disrupts basic cell function and causes a myriad of phenotypes in this family. The aim of the current grant is to develop molecular and analytical techniques that will advance our understanding of CharcotMarieTooth disease, limbgirdle muscular dystrophy and other neuromuscular disorders. The suggested training will provide the PI with skills necessary to investigate the clinical and basic molecular pathogenesis of these disorders and aid in the development of novel treatment protocols.