The Clinical Neurogenetics Unit research program is focused on identification and characterization of genes and genetic mechanisms involved in hereditary a) movement disorders, b) neuromuscular disorders, and c) prion diseases. Major findings: A clinically and pathologically distinct type of cardioskeletal myopathy is associated with mutations in the desmin gene: eight novel causative mutations have now been identified and described, and each mutation tested in a cell culture expression system. Digenic inheritance of malignant hyperthermia was established in a large American family with a novel mutation identified in the RYR1 gene on chromosome 19 and a significant linkage to a locus on chromosome 7q. An unusual phenotype with myoclonus, seizures and unique distribution of prion protein plaques in the cortex is associated with a novel H187R mutation in the prion protein (PRNP) gene. World distribution of hereditary prion encephalopathy caused by the PRNP E200K mutation indicate that both founder effect and new mutations determine the current geographic distribution. Genetically predetermined susceptibility to kuru is tightly linked to a M/V polymorphism in the PRNP gene. A novel mutation in exon 3B of the proteolipid protein (PLP) gene was identified as the cause of a late-onset spastic paraplegia with variable expression in heterozygotes.
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