Tuberous sclerosis is a dominantly inherited disease which is characterized by seizures, dermatologic changes, mental retardation, occurrence of tumors, most commonly in the brain, kidney and heart. Neither the mutant gene which gives rise to Tuberous sclerosis nor its products have been characterized. The purpose of our study is to identify a genetic marker which can be shown to be linked to the Tuberous sclerosis (TS) gene and to be inherited along with this gene. Blood samples from 6 three generation TS families collected by us and 16 families collected by our collaborators in Great Britain, have been analyzed using polymorphic genetic markers. 22 markers distributed on 11 chromosomes have been analyzed. Based on these analyses we have evidence that a TS gene is most likely located on human chromosome 9. This evidence is a lod score of over 4 for the TS gene and a marker on human chromosome 9. Analysis of the combined marker data and TS, using a maximum likelihood distribution analysis, indicates that TS is at least 35 times more likely to be on chromosome 9 than on any other chromosome. Studies need to be carried out particularly to address the problem of heterogenity in TS. We plan to collect samples from families with TS and analyze a wider range of polymorphic probes since TS may be due to mutations at more than one gene locus. Additional polymorphic markers must be derived from human chromosome 9. To do this we are isolating unique sequence probes from chromosome 9 libraries. These probes and other available gene probes, are being more precisely regionally assigned on human chromosome 9 using somatic cell hybrids recently developed which contain pieces of human chromosome 9. Lymphoblastoid cell lines will be derived from patients with TS and used to produce hybrids. Genetic marker information will be used to determine whether the normal or the mutant chromosome 9 is retained in the hybrid. Ultimately, through utilization of cosmid libraries and comparison of normal and mutant DNA and mRNA in normal and affected tissues, we will try to isolate the specific defective gene.
