Journal Article

Pathological mutations in <i>TSC1</i> and <i>TSC2</i> disrupt the interaction between hamartin and tuberin

Angela K. Hodges, Shaowei Li, Julie Maynard, Lee Parry, Richard Braverman, Jeremy P. Cheadle, Jeffrey E. DeClue and Julian R. Sampson

in Human Molecular Genetics

Volume 10, issue 25, pages 2899-2905
Published in print December 2001 | ISSN: 0964-6906
Published online December 2001 | e-ISSN: 1460-2083 | DOI:
Pathological mutations in TSC1 and TSC2 disrupt the interaction between hamartin and tuberin

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Critical functions of hamartin and tuberin, encoded by the TSC1 and TSC2 genes, are likely to be closely linked. The proteins interact directly with one another and mutations affecting either gene result in the tuberous sclerosis phenotype. However, the regions of hamartin and tuberin that interact have not been well defined, and the relationship between their interaction and the pathogenesis of tuberous sclerosis has not been explored. To address these issues a series of hamartin and tuberin constructs were used to assay for interaction in the yeast two-hybrid system. Hamartin (amino acids 302–430) and tuberin (amino acids 1–418) interacted strongly with one another. A region of tuberin encoding a putative coiled-coil (amino acids 346–371) was necessary but not sufficient to mediate the interaction with hamartin, as more N-terminal residues were also required. A region of hamartin (amino acids 719–998) predicted to encode coiled-coils was capable of oligermerization but was not important for the interaction with tuberin. Subtle, non-truncating mutations identified in patients with tuberous sclerosis and located within the putative binding regions of hamartin (N198_F199delinsI;593–595delACT) or tuberin (G294E and I365del), abolished or dramatically reduced interaction of the proteins as assessed by yeast two-hybrid assays and by co-immunoprecipitation of the full-length proteins from Cos7 cells. In contrast, three non-pathogenic missense polymorphisms of tuberin (R261W, M286V, R367Q) in the same region as the disease-causing TSC2 mutations did not. These results indicate a requirement for interaction in critical growth suppressing functions of hamartin and tuberin.

Journal Article.  5845 words.  Illustrated.

Subjects: Genetics and Genomics

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