{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T19:14:35Z","timestamp":1760728475830,"version":"build-2065373602"},"reference-count":21,"publisher":"BMJ","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"published-print":{"date-parts":[[1998,12]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1136\/jmg.35.12.969","type":"journal-article","created":{"date-parts":[[2008,11,10]],"date-time":"2008-11-10T15:37:21Z","timestamp":1226331441000},"page":"969-972","source":"Crossref","is-referenced-by-count":26,"title":["Mutations in the TSC1 gene account for a minority of patients with tuberous sclerosis."],"prefix":"10.1136","volume":"35","author":[{"given":"J B","family":"Ali","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T","family":"Sepp","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S","family":"Ward","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A J","family":"Green","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J R","family":"Yates","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[1998,12,1]]},"reference":[{"key":"ref_1","article-title":"Tuberous sclerosis","author":"Gomez, M.R.","year":"1988","unstructured":"Gomez MR, ed. Tuberous sclerosis. 2nd ed. New York: Raven Press, 1988.","edition":"2nd ed"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1111\/j.1749-6632.1991.tb37754.x","article-title":"Epidemiology of tuberous sclerosis","volume":"615","author":"Osborne, J.P.; Fryer, A.; Webb, D.","year":"1991","unstructured":"Osborne JP, Fryer A, Webb D. Epidemiology of tuberous sclerosis. Ann NYAcad Sci 1991;615:125-7.","journal-title":"Ann NYAcad Sci"},{"key":"ref_3","first-page":"107","article-title":"Two loci for tuberous sclerosis: one on 9q34 and one on 16pl3","volume":"58","author":"Povey, S.; Burley, M.W.; Attwood, J.","year":"1994","unstructured":"Povey S, Burley MW, Attwood J, et al. Two loci for tuberous sclerosis: one on 9q34 and one on 16pl3. Ann Hum Genet 1994;58: 107-27."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1305","DOI":"10.1016\/0092-8674(93)90618-Z","article-title":"European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16","volume":"75","year":"1993","unstructured":"European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993;75:1305-15.","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1093\/hmg\/4.8.1471","article-title":"A de novo frame-shift mutation in the tuberin gene","volume":"4","author":"Kumar, A.; Wolpert, C.; Kandt, R.S.","year":"1995","unstructured":"Kumar A, Wolpert C, Kandt RS, et al. A de novo frame-shift mutation in the tuberin gene. Hum Mol Genet 1995;4: 1471 - 2.","journal-title":"Hum Mol Genet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2295","DOI":"10.1093\/hmg\/4.12.2295","article-title":"Mutation analysis of the TSC2 gene in an African-American family","volume":"4","author":"Kumar, A.; Kandt, R.S.; Wolpert, C.; Roses, A.D.; Pericak-Vance, M.A.; Gilbert, JR","year":"1995","unstructured":"Kumar A, Kandt RS, Wolpert C, Roses AD, Pericak-Vance MA, Gilbert JR. Mutation analysis of the TSC2 gene in an African-American family. Hum Mol Genet 1995;4:2295-8.","journal-title":"Hum Mol Genet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1136\/jmg.33.1.47","article-title":"Identification of a nonsense mutation at the 5' end of the TSC2 gene in a family with a presumptive diagnosis of tuberous sclerosis complex","volume":"33","author":"Vrtel, R.; Verhoef, S.; Bouman, K.","year":"1996","unstructured":"Vrtel R, Verhoef S, Bouman K, et al. Identification of a nonsense mutation at the 5' end of the TSC2 gene in a family with a presumptive diagnosis of tuberous sclerosis complex. I Med Genet 1996;33:47-51.","journal-title":"I Med Genet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1093\/hmg\/5.2.249","article-title":"Novel mutations detected in the TSC2 gene from both sporadic and familial TSC patients","volume":"5","author":"Wilson, P.J.; Ramesh, V.; Kristiansen, A.","year":"1996","unstructured":"Wilson PJ, Ramesh V, Kristiansen A, et al. Novel mutations detected in the TSC2 gene from both sporadic and familial TSC patients. Hum Mol Genet 1996;5:249-56.","journal-title":"Hum Mol Genet"},{"key":"ref_9","first-page":"23","article-title":"Mutations and polymorphisms in the tuberous sclerosis complex gene on chromosome 16","volume":"9","author":"Au, K.S.; Rodriguez, J.A.; Rodriguez, E.; Dobyns, W.B.; Delgado, M.R.; Northrup, H.","year":"1997","unstructured":"Au KS, Rodriguez JA, Rodriguez E, Dobyns WB, Delgado MR, Northrup H. Mutations and polymorphisms in the tuberous sclerosis complex gene on chromosome 16. Hum Mutat 1997;9:23-9."},{"key":"ref_10","first-page":"192","article-title":"Loss of heterozygosity on chromosome 16pl3.3 in hamartomas from tuberous sclerosis patients","volume":"6","author":"Green, A.J.; Smith, M.; Yates, J.R.W.","year":"1994","unstructured":"Green AJ, Smith M, Yates JRW. Loss of heterozygosity on chromosome 16pl3.3 in hamartomas from tuberous sclerosis patients. Nat Genet 1994;6:192-6.","journal-title":"Nat Genet"},{"key":"ref_11","first-page":"659","article-title":"Evidence that the gene for tuberous sclerosis is on chromosome 9","volume":"i:","author":"Fryer, A.E.; Chalmers, A.; Connor, J.M.","year":"1987","unstructured":"Fryer AE, Chalmers A, Connor JM, et al. Evidence that the gene for tuberous sclerosis is on chromosome 9. Lancet 1987;i:659-61.","journal-title":"Lancet"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1833","DOI":"10.1093\/hmg\/3.10.1833","article-title":"The tuberous sclerosis gene on chromosome 9q34 acts as a growth suppressor","volume":"3","author":"Green, A.J.; Johnson, P.H.; Yates, J.R.W.","year":"1994","unstructured":"Green AJ, Johnson PH, Yates JRW. The tuberous sclerosis gene on chromosome 9q34 acts as a growth suppressor. Hum Mol Genet 1994;3:1833-4.","journal-title":"Hum Mol Genet"},{"issue":"34","key":"ref_13","doi-asserted-by":"crossref","first-page":"1829","DOI":"10.1093\/hmg\/3.10.1829","article-title":"loss of heterozygosity in a tuberous sclerosis astrocytoma suggests a growth suppressor-like activity also for the TSC1 gene","volume":"9","author":"Carbonara, C.; Longa, L.; Grosso, E.","year":"1994","unstructured":"Carbonara C, Longa L, Grosso E, et al. 9q34 loss of heterozygosity in a tuberous sclerosis astrocytoma suggests a growth suppressor-like activity also for the TSC1 gene. Hum Mol Genet 1994;3:1829-32.","journal-title":"Hum Mol Genet"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1136\/jmg.33.11.962","article-title":"Loss of heterozygosity in tuberous sclerosis hamartomas","volume":"33","author":"Sepp, T.; Yates, J.R.W.; Green, A.J.","year":"1996","unstructured":"Sepp T, Yates JRW, Green AJ. Loss of heterozygosity in tuberous sclerosis hamartomas. J Med Genet 1996;33:962-4.","journal-title":"J Med Genet"},{"key":"ref_15","first-page":"400","article-title":"Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions","volume":"59","author":"Henske, L.P.; Scheithauer, B.W.; Short, M.P.","year":"1996","unstructured":"Henske LP, Scheithauer BW, Short MP, et al. Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. Am J Hum Genet 1996;59:400-6.","journal-title":"Am J Hum Genet"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1126\/science.277.5327.805","article-title":"The TSC 1 Consortium. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34","volume":"277","year":"1997","unstructured":"The TSC 1 Consortium. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997;277: 805-8.","journal-title":"Science"},{"key":"ref_17","first-page":"615","article-title":"Phenotypes of the tuberous sclerosis complex with a revision of diagnostic criteria","author":"Gomez, M.R.","year":"1991","unstructured":"Gomez MR. Phenotypes of the tuberous sclerosis complex with a revision of diagnostic criteria. Ann NY Acad Sci 1991;615: 1-7.","journal-title":"Ann NY Acad Sci"},{"key":"ref_18","article-title":"Molecular cloning: a laboratory manual","author":"Maniatis, T.M.; Fritsch, E.F.; Sambrook, J.","year":"1982","unstructured":"Maniatis TM, Fritsch EF, Sambrook J. Molecular cloning: a laboratory manual. New York: Cold Spring Harbour Press, 1982."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"874","DOI":"10.1016\/0888-7543(89)90129-8","article-title":"Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction","volume":"5","author":"Orita, M.; Suzuki, Y.; Sekiya, T.; Hayashi, K.","year":"1989","unstructured":"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;5:874-9.","journal-title":"Genomics"},{"key":"ref_20","first-page":"10325","article-title":"Conformation-sensitive gel electrophoresis for rapid detection of single-base differences in double-stranded PCR products and DNA fragments: evidence for solvent-induced bends","volume-title":"DNA heteroduplexes. Proc Natl Acad Sci USA","volume":"90","author":"Ganguly, A.; Rock, M.J.; Prockop, D.J.","year":"1993","unstructured":"Ganguly A, Rock MJ, Prockop DJ. 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 USA 1993;90:10325-9."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2155","DOI":"10.1093\/hmg\/6.12.2155","article-title":"Molecular genetic and phenotypic analysis reveals differences between TSCI and TSC2 associated familial and sporadic tuberous sclerosis","volume":"6","author":"Jones, A.C.; Daniells, C.E.; Snell, R.G.","year":"1997","unstructured":"Jones AC, Daniells CE, Snell RG, et al. Molecular genetic and phenotypic analysis reveals differences between TSCI and TSC2 associated familial and sporadic tuberous sclerosis. 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