The Clinical Neurogenetics research program is focused on identification and characterization of genes and genetic mechanisms involved in hereditary movement and neuromuscular disorders. ? ? MYOFIBRILLAR MYOPATHIES: We have previously identified desmin gene as the cause of cardiac and skeletal myopathies. To-date, 42 mutations in this gene have been proven pathogenic. The pathogenic potentials correlate with the type and location of desmin mutations: those within the highly conserved 2B helical domain are especially damaging since 2B controls the integrity of the alpha-helix and is responsible for desmin filament assembly and stability. Pathogenic mechanisms of mutations in non-helical carboxy-terminal tail domain that also cause cardiac and skeletal myopathy remain unknown. We have identified and characterized mutations in Myotilin and ZASP, two other genes causing myofibrillar myopathy that is phenotypically distinct from desminopathy. ? ? PHENOTYPIC AND FUNCTIONAL ANALYSIS OF GLYCYL-tRNA SYNTHETASE (GARS) MUTATIONS IN dSMA-V/CMT2D TYPE OF PERIPHERAL NEUROPATHY: We have previously identified a gene causing atrophy in thenar and first dorsal interosseus muscles and a clinical continuum of predominantly motor distal neuronopathy/axonopathy with mild to moderate sensory involvement. Functional analyses of disease-associated GARS mutations have shown that the mutant GARS protein mislocalizes in neuronal cells so that endogenous GARS-associated granules are present in the neurite projections. The results suggest that mutant GARS is expressed in peripheral axons and may play a key role in dSMA-V/CMT2D pathogenesis. ? ? CHROMOSOMAL MAPPING OF GENES CAUSING ESSENTIAL TREMOR: We have identified, obtained informed consent, clinically evaluated and collected blood samples from members of ten American families with a tremor or tremor/dystonia phenotype. Genetic linkage to a region on chromosome 6p23 was established in two families with a combined NPL-all score 3.125 (P=0.0008), multipoint LOD score 4.248, and maximal two-point LOD score 2.70. Haplotype analysis led to the identification of a 600-kB interval shared by both families. Mutation analysis of coding exons in 14 genes discovered numerous sequence variants, three of which predicted a change of the encoded amino acid. Functional studies with attempts to implicate these genes in ET pathogenesis are under way. A new promising locus on chromosome 11p15 linked to tremor in three other American families suffering of ET is under study.? ? NOVEL HIGHLY EFFICIENT TECHNIQUE FOR MUTATION-DETECTION ANALYSIS OF LARGE GENES. ANALYSIS OF THE RYANODINE RECEPTOR TYPE 1 (RYR1) GENE ASSOCIATED WITH MALIGNANT HYPERTHERMIA: We developed a reliable genetic screening strategy based on Denaturing high-performance liquid chromatography (DHPLC) analysis of RNA samples extracted from the biopsied skeletal muscle followed by cDNA sequencing - as a method of choice for RYR1 mutation detection and identification in patients with Malignant hyperthermia (MH). This methodology significantly increased the mutation-detection rate from 25% to 70% and allowed to identify nine novel RYR1 mutations causing malignant hyperthermia in North-American populations.? ? MUTATIONS IN UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) GENE CAUSING HEREDITARY INCLUSION BODY MYOPATHY: Mutations in the GNE gene were identified in Caucasian, Indian and Greek families thus expanding the ethnic spectrum of the GNE mutation-associated myopathy. Molecular disease mechanisms involving hypoglycosylation of alpha-dystroglycan are under evaluation.
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