http://repub.eur.nl/res/aut/1934/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/9088/ 1999-01-01T00:00:00Z Tuberous sclerosis complex is an inherited tumour suppressor syndrome, caused by a mutation in either the TSC1 or TSC2 gene. The disease is characterised by a broad phenotypic spectrum that can include seizures, mental retardation, renal dysfunction, and dermatological abnormalities. The TSC1 gene was recently identified and has 23 exons, spanning 45 kb of genomic DNA, and encoding an 8.6 kb mRNA. After screening all 21 coding exons in our collection of 225 unrelated patients, only 29 small mutations were detected, suggesting that TSC1 mutations are under-represented among TSC patients. Almost all TSC1 mutations were small changes leading to a truncated protein, except for a splice site mutation and two in frame deletions in exon 7 and exon 15. No clear difference was observed in the clinical phenotype of patients with an in frame deletion or a frameshift or nonsense mutation. We found the disease causing mutation in 13% of our unrelated set of TSC patients, with more than half of the mutations clustered in exons 15 and 17, and no obvious under-representation of mutations among sporadic cases. In conclusion, we find no support for a genotype-phenotype correlation for the group of TSC1 patients compared to the overall population of TSC patients. http://repub.eur.nl/res/pub/9206/ 1999-01-01T00:00:00Z Tuberous sclerosis (TSC) is an autosomal dominant disorder characterized by a broad phenotypic spectrum that includes seizures, mental retardation, renal dysfunction and dermatological abnormalities. Mutations to either the TSC1 or TSC2 gene are responsible for the disease. The TSC1 gene encodes hamartin, a 130-kDa protein without significant homology to other known mammalian proteins. Analysis of the amino acid sequence of tuberin, the 200-kDa product of the TSC2 gene, identified a region with limited homology to GTPase-activating proteins. Previously, we demonstrated direct binding between tuberin and hamartin. Here we investigate this interaction in more detail. We show that the complex is predominantly cytosolic and may contain additional, as yet uncharacterized components alongside tuberin and hamartin. Furthermore, because oligomerization of the hamartin carboxyl-terminal coiled coil domain was inhibited by the presence of tuberin, we propose that tuberin acts as a chaperone, preventing hamartin self-aggregation. http://repub.eur.nl/res/pub/13665/ 1998-09-16T00:00:00Z 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. http://repub.eur.nl/res/pub/8818/ 1998-01-01T00:00:00Z Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by a mutation in either the TSC1 or TSC2 tumour suppressor gene. The disease is characterized by a broad phenotypic spectrum that can include seizures, mental retardation, renal dysfunction and dermatological abnormalities. TSC2 encodes tuberin, a putative GTPase activating protein for rap1 and rab5. The TSC1 gene was recently identified and codes for hamartin, a novel protein with no significant homology to tuberin or any other known vertebrate protein. Here, we show that hamartin and tuberin associate physically in vivo and that the interaction is mediated by predicted coiled-coil domains. Our data suggest that hamartin and tuberin function in the same complex rather than in separate pathways.