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Abstract

Abstract 

  1. Tuberous sclerosis is a multisystem hamartomatosis that is transmitted as an autosomal dominant trait with highly variable expression. Prevalence among newborns is estimated to be over 1 in 10,000 and is not thought to show significant geographic variation.

  2. Frequent manifestations of tuberous sclerosis include seizures, intellectual handicap, behavioral problems, a variety of skin lesions, and renal angiomyolipomas and cysts. Cardiac rhabdomyomas and hepatic angiomas are also common, but usually asymptomatic. The lungs and endocrine system are less frequently involved. Management is directed toward the early detection and treatment of important medical and psychological complications and the provision of genetic counseling.

  3. Two tuberous sclerosis-determining genes have been identified by positional cloning and are termed TSC1 and TSC2. A wide range of inactivating germ line mutations occur in patients with tuberous sclerosis. Demonstration of loss of heterozygosity or intragenic mutations affecting the corresponding wild-type allele in hamartomas indicates that both genes function as Knudson-type tumor suppressors.

  4. The TSC1 and TSC2 encoded proteins hamartin and tuberin are not homologous but interact directly with one another to form a largely cytosolic complex. Their cellular roles are not well understood.

  5. The Eker rat is a naturally occurring model of TSC2 inactivation. Its recognition has facilitated direct experimental confirmation of the tumour suppressor properties of TSC2. The gigas phenotype in Drosophila results from inactivating mutations of a gene orthologous to TSC2. Homozygous gigas −/− cells exhibit a phenotype of cellular hypertrophy and endoreduplication of DNA.

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