Journal Article

The GAP-Related Domain of Tuberin, the Product of the <i>TSC2</i> Gene, is a Target for Missense Mutations in Tuberous Sclerosis

Magitha M. Maheshwar, Jeremy P. Cheadle, Alistair C. Jones, Jenny Myring, Alan E. Fryer, Peter C. Harris and Julian R. Sampson

in Human Molecular Genetics

Volume 6, issue 11, pages 1991-1996
Published in print October 1997 | ISSN: 0964-6906
Published online October 1997 | e-ISSN: 1460-2083 | DOI:
The GAP-Related Domain of Tuberin, the Product of the TSC2 Gene, is a Target for Missense Mutations in Tuberous Sclerosis

Show Summary Details


Tuberous sclerosis is an autosomal dominant trait in which the dysregulation of cellular proliferation and differentiation results in the development of hamar-tomatous growths in many organs. The TSC2 gene is one of two genes determining tuberous sclerosis. Inactivating germline mutations of TSC2 in patients with tuberous sclerosis and somatic loss of heterozygosity at the TSC2 locus in the associated hamartomas indicate that TSC2 functions as a tumour suppressor gene and that loss of function is critical to expression of the tuberous sclerosis phenotype. The TSC2 product, tuberin, has a region of homology with the GTPase activating protein rap1GAP and stimulates the GTPase activity of rap1a and rab5a in vitro. Here we show that the region of homology between tuberin and human rap1GAP and the murine GAP mSpa1 is more extensive than previously reported and spans ∼160 amino acid residues encoded within exons 34–38 of the TSC2 gene. Single strand conformation polymorphism analysis of these exons in 173 unrelated patients with tuberous sclerosis and direct sequencing of variant conformers together with study of additional family members enabled characterisation of disease associated mutations in 14 cases. Missense mutations, which occurred in exons 36, 37 and 38 were identified in eight cases, four of whom shared the same recurrent change P1675L. Each of the five different missense mutations identified was shown to occur de novo in at least one sporadic case of tuberous sclerosis. The high proportion of missense mutations detected in the region of the TSC2 gene encoding the GAP-related domain supports its key role in the regulation of cellular growth.

Journal Article.  3925 words.  Illustrated.

Subjects: Genetics and Genomics

Full text: subscription required

How to subscribe Recommend to my Librarian

Users without a subscription are not able to see the full content. Please, subscribe or login to access all content.