Tuberous Sclerosis Complex I: gene identification and characterisation

This thesis describes the identification and the characterisation of the gene involved in tuberous sclerosis complex (TSC) on chromosome 9 (TSCl). For tItis purpose we used the positional cloning approach, a strategy by which many other disease genes, including the TSC2 gene on chromosome 16, have been isolated in the past years. The identification of the TSCI gene has taken 10 years of search and involved the cloning of the entire 1.5 Mb candidate region. Tuberous sclerosis is characterised by the widespread development of distinctive tumours (hamartomas) in many different tissues, and a broad phenotypic spectnl1u which lllay often include disturbed mental function, renal problems and dermatological abnormalities. TSC has an estimated prevalence of 1/6000 and occurs when either one of the TSCI or TSC2 tumour suppressor genes is inactivated. Mutations in the TSCI and TSC2 genes cause a velY similar clinical phenotype, suggesting that both genes play a closely related role in a still undetenllined biological process. Evidence for linkage between TSC and markers on cluomosome 9q34 had already been found in 1987. A consensus TSCI interval was defined in 1994, spanning approximately 1.5 Mb of genontic DNA. Refining the critical interval in affected individuals proved to be difficult, because of conflicting recombinant data in TSC families.