MOLECULAR STUDIES IN TUBEROUS SCLEROSIS

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Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with a high mutation rate which affects numerous organ systems. TS is characterized by hamartomas and harmartias and symptoms can vary from benign skin macules to mental retardation with epilepsy to premature death. The estimated prevalence of TSC is 1 per 10,000. TSC is a heterogeneous disorder. In 1987 genetic linkage was demonstrated between TSC and the ABO blood group on chromosome 9q34. Approximately one third of TSC families seem to be linked to the 9q loci. More recently this laboratory, using families clearly unlinked to the 9q loci, has shown linkage between the D16S283 marker, located at chromosome 16p13, and a large group of TSC families. Progress in isolating the 9q34 TSC gene has proceeded relatively slowly primarily because of family heterogeneity. Recent identification of a second TSC loci at 16p13, which includes the majority of the TSC families, allows the clarification of these issues and should greatly accelerate progress in isolating the 9q TSC gene. Although TSC was first linked to 9q six years ago all that could be said until recently is that the disease loci lay in a region of approximately 20 cM distal to D9S125 in 9q34. Recent analyses have, however, localized the chromosome 9 TSC loci to a region of approximately 2 cM flanked proximally by DBH and distally by D9S114. Efforts to further refine the TSC loci by developing new markers are presently underway. With the isolation of close flanking markers the chromosome 9 TSC region may be mapped using pulse field electrophoresis and Yeast Artificial Chromosomes (YAC)'s isolated from the new CEPH megabase library and existing YAC libraries. The TSC region will be physically clone using Yacs and a cosmic contig encompassing the TSC locus. New markers will be generated, genes contained within the region will be isolated and tested as TSC candidate genes.