Abstract
Tuberous sclerosis (TSC) is an autosomal dominant disorder characterised by tumour-like malformations (hamartomas) of the brain, skin, and other organs, often associated with seizures and learning disability. There is genetic heterogeneity with loci for TSC on chromosomes 9q34 (TSC1) and 16p13.3 (TSC2). The recently cloned TSC1 gene has 23 exons spanning some 40 kb of genomic DNA with an 8.6 kb transcript. We now report the results of mutation screening by SSCP and heteroduplex analysis of genomic DNA for all 21 coding exons of TSC1 in 83 unrelated cases of tuberous sclerosis. TSC1 gene mutations were found in 16 of the 83 cases (19%). These comprised base substitutions, small insertions, or small deletions giving rise to six nonsense mutations, eight frameshifts, and two splice site mutations, all of which would be expected to result in a truncated or absent protein. In the 10 cases predicted to have TSC1 mutations by linkage analysis or loss of heterozygosity studies, the mutation was identified in eight (80%). In the remaining 73 unassigned cases, only eight mutations were found (11%). From these data we estimate that TSC1 mutations accounted for 24% of the cases in this sample (and an estimated 22% of all TSC cases). This contrasts with data from linkage studies suggesting that TSC1 and TSC2 mutations account for approximately equal numbers of families.
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Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Au K. S., Rodriguez J. A., Rodriguez E., Jr, Dobyns W. B., Delgado M. R., Northrup H. Mutations and polymorphisms in the tuberous sclerosis complex gene on chromosome 16. Hum Mutat. 1997;9(1):23–29. doi: 10.1002/(SICI)1098-1004(1997)9:1<23::AID-HUMU4>3.0.CO;2-Q. [DOI] [PubMed] [Google Scholar]
- Carbonara C., Longa L., Grosso E., Borrone C., Garrè M. G., Brisigotti M., Migone N. 9q34 loss of heterozygosity in a tuberous sclerosis astrocytoma suggests a growth suppressor-like activity also for the TSC1 gene. Hum Mol Genet. 1994 Oct;3(10):1829–1832. doi: 10.1093/hmg/3.10.1829. [DOI] [PubMed] [Google Scholar]
- Fryer A. E., Chalmers A., Connor J. M., Fraser I., Povey S., Yates A. D., Yates J. R., Osborne J. P. Evidence that the gene for tuberous sclerosis is on chromosome 9. Lancet. 1987 Mar 21;1(8534):659–661. doi: 10.1016/s0140-6736(87)90416-8. [DOI] [PubMed] [Google Scholar]
- Ganguly A., Rock M. J., Prockop D. J. Conformation-sensitive gel electrophoresis for rapid detection of single-base differences in double-stranded PCR products and DNA fragments: evidence for solvent-induced bends in DNA heteroduplexes. Proc Natl Acad Sci U S A. 1993 Nov 1;90(21):10325–10329. doi: 10.1073/pnas.90.21.10325. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gomez M. R. Phenotypes of the tuberous sclerosis complex with a revision of diagnostic criteria. Ann N Y Acad Sci. 1991;615:1–7. doi: 10.1111/j.1749-6632.1991.tb37742.x. [DOI] [PubMed] [Google Scholar]
- Green A. J., Johnson P. H., Yates J. R. The tuberous sclerosis gene on chromosome 9q34 acts as a growth suppressor. Hum Mol Genet. 1994 Oct;3(10):1833–1834. doi: 10.1093/hmg/3.10.1833. [DOI] [PubMed] [Google Scholar]
- Henske E. P., Scheithauer B. W., Short M. P., Wollmann R., Nahmias J., Hornigold N., van Slegtenhorst M., Welsh C. T., Kwiatkowski D. J. Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. Am J Hum Genet. 1996 Aug;59(2):400–406. [PMC free article] [PubMed] [Google Scholar]
- Jones A. C., Daniells C. E., Snell R. G., Tachataki M., Idziaszczyk S. A., Krawczak M., Sampson J. R., Cheadle J. P. Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis. Hum Mol Genet. 1997 Nov;6(12):2155–2161. doi: 10.1093/hmg/6.12.2155. [DOI] [PubMed] [Google Scholar]
- Kumar A., Kandt R. S., Wolpert C., Roses A. D., Pericak-Vance M. A., Gilbert J. R. Mutation analysis of the TSC2 gene in an African-American family. Hum Mol Genet. 1995 Dec;4(12):2295–2298. doi: 10.1093/hmg/4.12.2295. [DOI] [PubMed] [Google Scholar]
- Kumar A., Wolpert C., Kandt R. S., Segal J., Pufky J., Roses A. D., Pericak-Vance M. A., Gilbert J. R. A de novo frame-shift mutation in the tuberin gene. Hum Mol Genet. 1995 Aug;4(8):1471–1472. doi: 10.1093/hmg/4.8.1471. [DOI] [PubMed] [Google Scholar]
- Orita M., Suzuki Y., Sekiya T., Hayashi K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics. 1989 Nov;5(4):874–879. doi: 10.1016/0888-7543(89)90129-8. [DOI] [PubMed] [Google Scholar]
- Osborne J. P., Fryer A., Webb D. Epidemiology of tuberous sclerosis. Ann N Y Acad Sci. 1991;615:125–127. doi: 10.1111/j.1749-6632.1991.tb37754.x. [DOI] [PubMed] [Google Scholar]
- Povey S., Burley M. W., Attwood J., Benham F., Hunt D., Jeremiah S. J., Franklin D., Gillett G., Malas S., Robson E. B. Two loci for tuberous sclerosis: one on 9q34 and one on 16p13. Ann Hum Genet. 1994 May;58(Pt 2):107–127. doi: 10.1111/j.1469-1809.1994.tb01881.x. [DOI] [PubMed] [Google Scholar]
- Sepp T., Yates J. R., Green A. J. Loss of heterozygosity in tuberous sclerosis hamartomas. J Med Genet. 1996 Nov;33(11):962–964. doi: 10.1136/jmg.33.11.962. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Vrtel R., Verhoef S., Bouman K., Maheshwar M. M., Nellist M., van Essen A. J., Bakker P. L., Hermans C. J., Bink-Boelkens M. T., van Elburg R. M. Identification of a nonsense mutation at the 5' end of the TSC2 gene in a family with a presumptive diagnosis of tuberous sclerosis complex. J Med Genet. 1996 Jan;33(1):47–51. doi: 10.1136/jmg.33.1.47. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wilson P. J., Ramesh V., Kristiansen A., Bove C., Jozwiak S., Kwiatkowski D. J., Short M. P., Haines J. L. Novel mutations detected in the TSC2 gene from both sporadic and familial TSC patients. Hum Mol Genet. 1996 Feb;5(2):249–256. doi: 10.1093/hmg/5.2.249. [DOI] [PubMed] [Google Scholar]
- van Bakel I., Sepp T., Ward S., Yates J. R., Green A. J. Mutations in the TSC2 gene: analysis of the complete coding sequence using the protein truncation test (PTT). Hum Mol Genet. 1997 Sep;6(9):1409–1414. doi: 10.1093/hmg/6.9.1409. [DOI] [PubMed] [Google Scholar]
- van Slegtenhorst M., de Hoogt R., Hermans C., Nellist M., Janssen B., Verhoef S., Lindhout D., van den Ouweland A., Halley D., Young J. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science. 1997 Aug 8;277(5327):805–808. doi: 10.1126/science.277.5327.805. [DOI] [PubMed] [Google Scholar]