ROLE OF TORSIN GENE FAMILY IN DYSTONIA AND GENETIC DETERMINANTS OF PENETRANCE

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Early onset torsin dystonia is a movement disorder inherited in an autosomal dominant manner with reduced penetrance, that is characterized by twisting muscle contractures. Symptoms are believed to result from abnormality in the basal ganglia. The gene for this disorder, DYTl has recently been cloned by our group and shown to contain a 3-bp deletion (GAG), removing a glutamic acid in a conserved region that is uniquely associated with affected status. In addition, this gene is related to three other highly homologous human genes (TORB, TRP1, TRP2). This proposal is aimed at characterizing the DYTl gene and its relatives, determining genetic factors that may influence the penetrance of the disease, and generating an authentic murine model for the disorder. The genomic structure of the Dytl and TORB genes will be fully characterized making possible efficient mutation screening, antibody production, and biochemical analyses in conjunction with the other cores and projects in this program. The TRP1 and TRP2 genes will be isolated from cDNA libraries, their expression patterns and chromosomal locations determined and scanned for involvement in other forms of dystonia using linkage analysis and non-9q34 linked families. If warranted, singled-stranded conformation polymorphism analysis (SSCP) and direct sequencing of RNA/PCR products will be used to detect mutations in these genes. Affected and unaffected gene carriers from a set of 20 DYTl linked families will be used in linkage studies to identify genes which modify the expression of the GAG deletion resulting in the high level (60-70%) of reduced penetrance among carriers of the mutation. Various candidate genes will be screened first then, if necessary, we will proceed to a full genome scan. We also propose to generate targeted transgenic mice where the mouse DYTl gene harboring the GAG deletion is introduced into the endogenous mouse locus by homologous recombination in ES cells. These animals will be analyzed for neuromorphological and behavioral phenotypes. The studies proposed here should help to elucidate how the deletion of Glu residue causes early onset dystonia and the genetic factors that may modify its expression. This knowledge should lead to a better understanding of basal ganglia function and possible therapeutic interventions that could result in milder phenotypes.