{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T11:10:24Z","timestamp":1792062624568,"version":"4.4.0"},"reference-count":69,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"5327","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Science"],"published-print":{"date-parts":[[1997,8,8]]},"abstract":"<jats:p>\n                    Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the widespread development of distinctive tumors termed hamartomas. TSC-determining loci have been mapped to chromosomes 9q34 (\n                    <jats:italic>TSC1<\/jats:italic>\n                    ) and 16p13 (\n                    <jats:italic>TSC2<\/jats:italic>\n                    ). The\n                    <jats:italic>TSC1<\/jats:italic>\n                    gene was identified from a 900-kilobase region containing at least 30 genes. The 8.6-kilobase\n                    <jats:italic>TSC1<\/jats:italic>\n                    transcript is widely expressed and encodes a protein of 130 kilodaltons (hamartin) that has homology to a putative yeast protein of unknown function. Thirty-two distinct mutations were identified in\n                    <jats:italic>TSC1<\/jats:italic>\n                    , 30 of which were truncating, and a single mutation (2105delAAAG) was seen in six apparently unrelated patients. In one of these six, a somatic mutation in the wild-type allele was found in a TSC-associated renal carcinoma, which suggests that hamartin acts as a tumor suppressor.\n                  <\/jats:p>","DOI":"10.1126\/science.277.5327.805","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T05:37:56Z","timestamp":1027748276000},"page":"805-808","source":"Crossref","is-referenced-by-count":1410,"title":["Identification of the Tuberous Sclerosis Gene\n                    <i>TSC1<\/i>\n                    on Chromosome 9q34"],"prefix":"10.1126","volume":"277","author":[{"given":"Marjon van","family":"Slegtenhorst","sequence":"first","affiliation":[{"name":"The TSC1  Consortium:"},{"name":"M. van Slegtenhorst, R. de Hoogt, C. Hermans, M. Nellist, B. Janssen, S. Verhoef, D. Lindhout, A. van den Ouweland, D. Halley, Department of Clinical Genetics, Erasmus University and University Hospital, Rotterdam, Netherlands."},{"name":"J. Young, M. Burley, S. Jeremiah, K. Woodward, J. Nahmias, M. Fox, R. Ekong, J. Wolfe, S. Povey, MRC Human Biochemical Genetics Unit and Galton Laboratory, University College of London, London NW1 2HE, UK."},{"name":"J. Osborne, University of Bath, Bath BA2 7AY, UK."},{"name":"R. G. Snell, J. P. Cheadle, A. C. Jones, M. Tachataki, D. Ravine, J. R. Sampson, Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, Wales, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald de","family":"Hoogt","sequence":"additional","affiliation":[{"name":"The TSC1  Consortium:"},{"name":"M. van Slegtenhorst, R. de Hoogt, C. Hermans, M. Nellist, B. Janssen, S. Verhoef, D. Lindhout, A. van den Ouweland, D. Halley, Department of Clinical Genetics, Erasmus University and University Hospital, Rotterdam, Netherlands."},{"name":"J. Young, M. Burley, S. Jeremiah, K. Woodward, J. Nahmias, M. Fox, R. Ekong, J. Wolfe, S. Povey, MRC Human Biochemical Genetics Unit and Galton Laboratory, University College of London, London NW1 2HE, UK."},{"name":"J. Osborne, University of Bath, Bath BA2 7AY, UK."},{"name":"R. G. Snell, J. P. Cheadle, A. C. Jones, M. Tachataki, D. Ravine, J. R. Sampson, Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, Wales, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Hermans","sequence":"additional","affiliation":[{"name":"The TSC1  Consortium:"},{"name":"M. van Slegtenhorst, R. de Hoogt, C. Hermans, M. Nellist, B. Janssen, S. Verhoef, D. Lindhout, A. van den Ouweland, D. Halley, Department of Clinical Genetics, Erasmus University and University Hospital, Rotterdam, Netherlands."},{"name":"J. Young, M. Burley, S. Jeremiah, K. Woodward, J. Nahmias, M. Fox, R. Ekong, J. Wolfe, S. Povey, MRC Human Biochemical Genetics Unit and Galton Laboratory, University College of London, London NW1 2HE, UK."},{"name":"J. Osborne, University of Bath, Bath BA2 7AY, UK."},{"name":"R. G. Snell, J. P. Cheadle, A. C. Jones, M. Tachataki, D. Ravine, J. R. Sampson, Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, Wales, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Nellist","sequence":"additional","affiliation":[{"name":"The TSC1  Consortium:"},{"name":"M. van Slegtenhorst, R. de Hoogt, C. Hermans, M. Nellist, B. Janssen, S. Verhoef, D. Lindhout, A. van den Ouweland, D. Halley, Department of Clinical Genetics, Erasmus University and University Hospital, Rotterdam, Netherlands."},{"name":"J. Young, M. Burley, S. Jeremiah, K. Woodward, J. Nahmias, M. Fox, R. Ekong, J. Wolfe, S. Povey, MRC Human Biochemical Genetics Unit and Galton Laboratory, University College of London, London NW1 2HE, UK."},{"name":"J. Osborne, University of Bath, Bath BA2 7AY, UK."},{"name":"R. G. Snell, J. P. Cheadle, A. C. Jones, M. Tachataki, D. Ravine, J. R. Sampson, Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, Wales, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart","family":"Janssen","sequence":"additional","affiliation":[{"name":"The TSC1  Consortium:"},{"name":"M. van Slegtenhorst, R. de Hoogt, C. Hermans, M. Nellist, B. Janssen, S. Verhoef, D. Lindhout, A. van den Ouweland, D. Halley, Department of Clinical Genetics, Erasmus University and University Hospital, Rotterdam, Netherlands."},{"name":"J. Young, M. Burley, S. Jeremiah, K. Woodward, J. Nahmias, M. Fox, R. Ekong, J. Wolfe, S. Povey, MRC Human Biochemical Genetics Unit and Galton Laboratory, University College of London, London NW1 2HE, UK."},{"name":"J. Osborne, University of Bath, Bath BA2 7AY, UK."},{"name":"R. G. Snell, J. P. Cheadle, A. C. Jones, M. Tachataki, D. Ravine, J. R. Sampson, Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, Wales, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Senno","family":"Verhoef","sequence":"additional","affiliation":[{"name":"The TSC1  Consortium:"},{"name":"M. van Slegtenhorst, R. de Hoogt, C. Hermans, M. Nellist, B. Janssen, S. Verhoef, D. Lindhout, A. van den Ouweland, D. Halley, Department of Clinical Genetics, Erasmus University and University Hospital, Rotterdam, Netherlands."},{"name":"J. Young, M. Burley, S. Jeremiah, K. Woodward, J. Nahmias, M. Fox, R. Ekong, J. Wolfe, S. Povey, MRC Human Biochemical Genetics Unit and Galton Laboratory, University College of London, London NW1 2HE, UK."},{"name":"J. Osborne, University of Bath, Bath BA2 7AY, UK."},{"name":"R. G. Snell, J. P. Cheadle, A. C. Jones, M. Tachataki, D. Ravine, J. R. Sampson, Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, Wales, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dick","family":"Lindhout","sequence":"additional","affiliation":[{"name":"The TSC1  Consortium:"},{"name":"M. van Slegtenhorst, R. de Hoogt, C. Hermans, M. Nellist, B. Janssen, S. Verhoef, D. Lindhout, A. van den Ouweland, D. Halley, Department of Clinical Genetics, Erasmus University and University Hospital, Rotterdam, Netherlands."},{"name":"J. Young, M. Burley, S. Jeremiah, K. Woodward, J. Nahmias, M. Fox, R. Ekong, J. Wolfe, S. Povey, MRC Human Biochemical Genetics Unit and Galton Laboratory, University College of London, London NW1 2HE, UK."},{"name":"J. Osborne, University of Bath, Bath BA2 7AY, UK."},{"name":"R. G. Snell, J. P. Cheadle, A. C. Jones, M. Tachataki, D. Ravine, J. R. Sampson, Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, Wales, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ans van den","family":"Ouweland","sequence":"additional","affiliation":[{"name":"The TSC1  Consortium:"},{"name":"M. van Slegtenhorst, R. de Hoogt, C. Hermans, M. Nellist, B. Janssen, S. Verhoef, D. Lindhout, A. van den Ouweland, D. Halley, Department of Clinical Genetics, Erasmus University and University Hospital, Rotterdam, Netherlands."},{"name":"J. Young, M. Burley, S. Jeremiah, K. Woodward, J. Nahmias, M. Fox, R. Ekong, J. Wolfe, S. Povey, MRC Human Biochemical Genetics Unit and Galton Laboratory, University College of London, London NW1 2HE, UK."},{"name":"J. Osborne, University of Bath, Bath BA2 7AY, UK."},{"name":"R. G. Snell, J. P. Cheadle, A. C. Jones, M. Tachataki, D. Ravine, J. R. Sampson, Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, Wales, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dicky","family":"Halley","sequence":"additional","affiliation":[{"name":"The TSC1  Consortium:"},{"name":"M. van Slegtenhorst, R. de Hoogt, C. Hermans, M. Nellist, B. Janssen, S. Verhoef, D. Lindhout, A. van den Ouweland, D. Halley, Department of Clinical Genetics, Erasmus University and University Hospital, Rotterdam, Netherlands."},{"name":"J. Young, M. Burley, S. Jeremiah, K. Woodward, J. Nahmias, M. Fox, R. Ekong, J. Wolfe, S. Povey, MRC Human Biochemical Genetics Unit and Galton Laboratory, University College of London, London NW1 2HE, UK."},{"name":"J. Osborne, University of Bath, Bath BA2 7AY, UK."},{"name":"R. G. Snell, J. P. Cheadle, A. C. Jones, M. Tachataki, D. Ravine, J. R. Sampson, Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, Wales, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet","family":"Young","sequence":"additional","affiliation":[{"name":"The TSC1  Consortium:"},{"name":"M. van Slegtenhorst, R. de Hoogt, C. Hermans, M. Nellist, B. Janssen, S. Verhoef, D. Lindhout, A. van den Ouweland, D. Halley, Department of Clinical Genetics, Erasmus University and University Hospital, Rotterdam, Netherlands."},{"name":"J. Young, M. Burley, S. Jeremiah, K. Woodward, J. Nahmias, M. Fox, R. Ekong, J. Wolfe, S. Povey, MRC Human Biochemical Genetics Unit and Galton Laboratory, University College of London, London NW1 2HE, UK."},{"name":"J. Osborne, University of Bath, Bath BA2 7AY, UK."},{"name":"R. G. Snell, J. P. Cheadle, A. C. Jones, M. Tachataki, D. Ravine, J. R. Sampson, Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, Wales, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariwyn","family":"Burley","sequence":"additional","affiliation":[{"name":"The TSC1  Consortium:"},{"name":"M. van Slegtenhorst, R. de Hoogt, C. Hermans, M. Nellist, B. Janssen, S. Verhoef, D. Lindhout, A. van den Ouweland, D. Halley, Department of Clinical Genetics, Erasmus University and University Hospital, Rotterdam, Netherlands."},{"name":"J. Young, M. Burley, S. Jeremiah, K. Woodward, J. Nahmias, M. Fox, R. Ekong, J. Wolfe, S. Povey, MRC Human Biochemical Genetics Unit and Galton Laboratory, University College of London, London NW1 2HE, UK."},{"name":"J. Osborne, University of Bath, Bath BA2 7AY, UK."},{"name":"R. G. Snell, J. P. Cheadle, A. C. Jones, M. Tachataki, D. Ravine, J. R. Sampson, Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, Wales, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Jeremiah","sequence":"additional","affiliation":[{"name":"The TSC1  Consortium:"},{"name":"M. van Slegtenhorst, R. de Hoogt, C. Hermans, M. Nellist, B. Janssen, S. Verhoef, D. Lindhout, A. van den Ouweland, D. Halley, Department of Clinical Genetics, Erasmus University and University Hospital, Rotterdam, Netherlands."},{"name":"J. Young, M. Burley, S. Jeremiah, K. Woodward, J. Nahmias, M. Fox, R. Ekong, J. Wolfe, S. Povey, MRC Human Biochemical Genetics Unit and Galton Laboratory, University College of London, London NW1 2HE, UK."},{"name":"J. Osborne, University of Bath, Bath BA2 7AY, UK."},{"name":"R. G. Snell, J. P. Cheadle, A. C. Jones, M. Tachataki, D. Ravine, J. R. Sampson, Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, Wales, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Woodward","sequence":"additional","affiliation":[{"name":"The TSC1  Consortium:"},{"name":"M. van Slegtenhorst, R. de Hoogt, C. Hermans, M. Nellist, B. Janssen, S. Verhoef, D. Lindhout, A. van den Ouweland, D. Halley, Department of Clinical Genetics, Erasmus University and University Hospital, Rotterdam, Netherlands."},{"name":"J. Young, M. Burley, S. Jeremiah, K. Woodward, J. Nahmias, M. Fox, R. Ekong, J. Wolfe, S. Povey, MRC Human Biochemical Genetics Unit and Galton Laboratory, University College of London, London NW1 2HE, UK."},{"name":"J. Osborne, University of Bath, Bath BA2 7AY, UK."},{"name":"R. G. Snell, J. P. Cheadle, A. C. Jones, M. Tachataki, D. Ravine, J. R. Sampson, Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, Wales, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Nahmias","sequence":"additional","affiliation":[{"name":"The TSC1  Consortium:"},{"name":"M. van Slegtenhorst, R. de Hoogt, C. Hermans, M. Nellist, B. Janssen, S. Verhoef, D. Lindhout, A. van den Ouweland, D. Halley, Department of Clinical Genetics, Erasmus University and University Hospital, Rotterdam, Netherlands."},{"name":"J. Young, M. Burley, S. Jeremiah, K. Woodward, J. Nahmias, M. Fox, R. Ekong, J. Wolfe, S. Povey, MRC Human Biochemical Genetics Unit and Galton Laboratory, University College of London, London NW1 2HE, UK."},{"name":"J. Osborne, University of Bath, Bath BA2 7AY, UK."},{"name":"R. G. Snell, J. P. Cheadle, A. C. Jones, M. Tachataki, D. Ravine, J. R. Sampson, Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, Wales, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Fox","sequence":"additional","affiliation":[{"name":"The TSC1  Consortium:"},{"name":"M. van Slegtenhorst, R. de Hoogt, C. Hermans, M. Nellist, B. Janssen, S. Verhoef, D. Lindhout, A. van den Ouweland, D. Halley, Department of Clinical Genetics, Erasmus University and University Hospital, Rotterdam, Netherlands."},{"name":"J. Young, M. Burley, S. Jeremiah, K. Woodward, J. Nahmias, M. Fox, R. Ekong, J. Wolfe, S. Povey, MRC Human Biochemical Genetics Unit and Galton Laboratory, University College of London, London NW1 2HE, UK."},{"name":"J. Osborne, University of Bath, Bath BA2 7AY, UK."},{"name":"R. G. Snell, J. P. Cheadle, A. C. Jones, M. Tachataki, D. Ravine, J. R. Sampson, Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, Wales, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosemary","family":"Ekong","sequence":"additional","affiliation":[{"name":"The TSC1  Consortium:"},{"name":"M. van Slegtenhorst, R. de Hoogt, C. Hermans, M. Nellist, B. Janssen, S. Verhoef, D. Lindhout, A. van den Ouweland, D. Halley, Department of Clinical Genetics, Erasmus University and University Hospital, Rotterdam, Netherlands."},{"name":"J. Young, M. Burley, S. Jeremiah, K. Woodward, J. Nahmias, M. Fox, R. Ekong, J. Wolfe, S. Povey, MRC Human Biochemical Genetics Unit and Galton Laboratory, University College of London, London NW1 2HE, UK."},{"name":"J. Osborne, University of Bath, Bath BA2 7AY, UK."},{"name":"R. G. Snell, J. P. Cheadle, A. C. Jones, M. Tachataki, D. Ravine, J. R. Sampson, Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, Wales, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Osborne","sequence":"additional","affiliation":[{"name":"The TSC1  Consortium:"},{"name":"M. van Slegtenhorst, R. de Hoogt, C. Hermans, M. Nellist, B. Janssen, S. Verhoef, D. Lindhout, A. van den Ouweland, D. Halley, Department of Clinical Genetics, Erasmus University and University Hospital, Rotterdam, Netherlands."},{"name":"J. Young, M. Burley, S. Jeremiah, K. Woodward, J. Nahmias, M. Fox, R. Ekong, J. Wolfe, S. Povey, MRC Human Biochemical Genetics Unit and Galton Laboratory, University College of London, London NW1 2HE, UK."},{"name":"J. Osborne, University of Bath, Bath BA2 7AY, UK."},{"name":"R. G. Snell, J. P. Cheadle, A. C. Jones, M. Tachataki, D. Ravine, J. R. Sampson, Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, Wales, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Wolfe","sequence":"additional","affiliation":[{"name":"The TSC1  Consortium:"},{"name":"M. van Slegtenhorst, R. de Hoogt, C. Hermans, M. Nellist, B. Janssen, S. Verhoef, D. Lindhout, A. van den Ouweland, D. Halley, Department of Clinical Genetics, Erasmus University and University Hospital, Rotterdam, Netherlands."},{"name":"J. Young, M. Burley, S. Jeremiah, K. Woodward, J. Nahmias, M. Fox, R. Ekong, J. Wolfe, S. Povey, MRC Human Biochemical Genetics Unit and Galton Laboratory, University College of London, London NW1 2HE, UK."},{"name":"J. Osborne, University of Bath, Bath BA2 7AY, UK."},{"name":"R. G. Snell, J. P. Cheadle, A. C. Jones, M. Tachataki, D. Ravine, J. R. Sampson, Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, Wales, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sue","family":"Povey","sequence":"additional","affiliation":[{"name":"The TSC1  Consortium:"},{"name":"M. van Slegtenhorst, R. de Hoogt, C. Hermans, M. Nellist, B. Janssen, S. Verhoef, D. Lindhout, A. van den Ouweland, D. Halley, Department of Clinical Genetics, Erasmus University and University Hospital, Rotterdam, Netherlands."},{"name":"J. Young, M. Burley, S. Jeremiah, K. Woodward, J. Nahmias, M. Fox, R. Ekong, J. Wolfe, S. Povey, MRC Human Biochemical Genetics Unit and Galton Laboratory, University College of London, London NW1 2HE, UK."},{"name":"J. Osborne, University of Bath, Bath BA2 7AY, UK."},{"name":"R. G. Snell, J. P. Cheadle, A. C. Jones, M. Tachataki, D. Ravine, J. R. Sampson, Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, Wales, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell G.","family":"Snell","sequence":"additional","affiliation":[{"name":"The TSC1  Consortium:"},{"name":"M. van Slegtenhorst, R. de Hoogt, C. Hermans, M. Nellist, B. Janssen, S. Verhoef, D. Lindhout, A. van den Ouweland, D. Halley, Department of Clinical Genetics, Erasmus University and University Hospital, Rotterdam, Netherlands."},{"name":"J. Young, M. Burley, S. Jeremiah, K. Woodward, J. Nahmias, M. Fox, R. Ekong, J. Wolfe, S. Povey, MRC Human Biochemical Genetics Unit and Galton Laboratory, University College of London, London NW1 2HE, UK."},{"name":"J. Osborne, University of Bath, Bath BA2 7AY, UK."},{"name":"R. G. Snell, J. P. Cheadle, A. C. Jones, M. Tachataki, D. Ravine, J. R. Sampson, Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, Wales, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy P.","family":"Cheadle","sequence":"additional","affiliation":[{"name":"The TSC1  Consortium:"},{"name":"M. van Slegtenhorst, R. de Hoogt, C. Hermans, M. Nellist, B. Janssen, S. Verhoef, D. Lindhout, A. van den Ouweland, D. Halley, Department of Clinical Genetics, Erasmus University and University Hospital, Rotterdam, Netherlands."},{"name":"J. Young, M. Burley, S. Jeremiah, K. Woodward, J. Nahmias, M. Fox, R. Ekong, J. Wolfe, S. Povey, MRC Human Biochemical Genetics Unit and Galton Laboratory, University College of London, London NW1 2HE, UK."},{"name":"J. Osborne, University of Bath, Bath BA2 7AY, UK."},{"name":"R. G. Snell, J. P. Cheadle, A. C. Jones, M. Tachataki, D. Ravine, J. R. Sampson, Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, Wales, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alistair C.","family":"Jones","sequence":"additional","affiliation":[{"name":"The TSC1  Consortium:"},{"name":"M. van Slegtenhorst, R. de Hoogt, C. Hermans, M. Nellist, B. Janssen, S. Verhoef, D. Lindhout, A. van den Ouweland, D. Halley, Department of Clinical Genetics, Erasmus University and University Hospital, Rotterdam, Netherlands."},{"name":"J. Young, M. Burley, S. Jeremiah, K. Woodward, J. Nahmias, M. Fox, R. Ekong, J. Wolfe, S. Povey, MRC Human Biochemical Genetics Unit and Galton Laboratory, University College of London, London NW1 2HE, UK."},{"name":"J. Osborne, University of Bath, Bath BA2 7AY, UK."},{"name":"R. G. Snell, J. P. Cheadle, A. C. Jones, M. Tachataki, D. Ravine, J. R. Sampson, Institute of Medical Genetics, University of Wales College of Medicine, Cardiff CF4 4XN, Wales, UK."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Tachataki","sequence":"additional","affiliation":[{"name":"The TSC1  Consortium:"},{"name":"M. van Slegtenhorst, R. de Hoogt, C. Hermans, M. Nellist, B. Janssen, S. Verhoef, D. Lindhout, A. van den Ouweland, D. Halley, Department of Clinical Genetics, Erasmus University and University Hospital, Rotterdam, Netherlands."},{"name":"J. Young, M. Burley, S. Jeremiah, K. Woodward, J. Nahmias, M. Fox, R. Ekong, J. Wolfe, S. Povey, MRC Human Biochemical Genetics Unit and Galton Laboratory, University College of London, London NW1 2HE, UK."},{"name":"J. Osborne, University of Bath, Bath BA2 7AY, UK."},{"name":"R. G. Snell, J. P. Cheadle, A. C. Jones, M. Tachataki, D. Ravine, J. R. 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Genet."},{"key":"e_1_3_1_15_2","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1002\/(SICI)1098-2264(199601)15:1<18::AID-GCC3>3.0.CO;2-7","volume":"15","author":"Carbonara C.","year":"1996","unstructured":"Carbonara C., et al., Genes Chromosomes Cancer 15, 18 (1996).","journal-title":"Genes Chromosomes Cancer"},{"key":"e_1_3_1_16_2","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1006\/geno.1997.4681","volume":"41","author":"Hornigold N.","year":"1997","unstructured":"Hornigold N., et al., Genomics 41, 385 (1997).","journal-title":"Genomics"},{"key":"e_1_3_1_17_2","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1159\/000133566","volume":"64","author":"Kwiatkowski D. J.","year":"1993","unstructured":"Kwiatkowski D. J., et al., Cytogenet. Cell Genet. 64, 93 (1993);","journal-title":"Cytogenet. Cell Genet."},{"key":"e_1_3_1_17_3","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1111\/j.1469-1809.1994.tb01887.x","volume":"58","author":"Povey S.","year":"1994","unstructured":"Povey S., et al., Ann. Hum. Genet. 58, 177 (1994).","journal-title":"Ann. Hum. Genet."},{"key":"e_1_3_1_18_2","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1136\/jmg.33.7.559","volume":"33","author":"Au K. S.","year":"1996","unstructured":"Au K. S., Murrell J., Buckler A., Blanton S. H., Northrup H., J. Med. Genet. 33, 559 (1996).","journal-title":"J. Med. Genet."},{"key":"e_1_3_1_19_2","unstructured":"The diagnosis of tuberous sclerosis was made according to standard diagnostic criteria (2). Blood samples (obtained after informed consent) were used for DNA preparation either directly or after creation of immortalized Epstein-Barr virus\u2013transformed lymphoblastoid cell lines. Linkage to the TSC1 region was inferred if a family demonstrated obligate recombination with markers within 2 centimorgans (cM) of TSC2 and had positive lod scores (logarithm of the odds ratio for linkage) in analyses with 9q34 markers (Fig. 1). Families providing critical recombinant events were analyzed with multiple markers from 9q34 and haplotype analysis was performed manually to identify the site of recombination."},{"key":"e_1_3_1_20_2","first-page":"764","volume":"49","author":"Haines J. L.","year":"1991","unstructured":"Haines J. L., et al., Am. J. Hum. Genet. 49, 764 (1991);","journal-title":"Am. J. Hum. Genet."},{"key":"e_1_3_1_20_3","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1136\/jmg.30.3.224","volume":"30","author":"Nellist M.","year":"1993","unstructured":"Nellist M., et al., J. Med. Genet. 30, 224 (1993).","journal-title":"J. Med. Genet."},{"key":"e_1_3_1_21_2","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1159\/000131529","volume":"28","author":"Jones C.","year":"1980","unstructured":"Jones C., Kao F. T., Taylor R. T., Cytogenet. Cell Genet. 28, 181 (1980).","journal-title":"Cytogenet. Cell Genet."},{"key":"e_1_3_1_22_2","unstructured":"Cosmid BAC or PAC DNA was digested with Pst I or Bam HI and a library of subclones was prepared in pSPL3 ["},{"key":"e_1_3_1_22_3","doi-asserted-by":"crossref","first-page":"4005","DOI":"10.1073\/pnas.88.9.4005","volume":"88","author":"Buckler A. J.","year":"1991","unstructured":"Buckler A. J., et al., Proc. Natl. Acad. Sci. U.S.A. 88, 4005 (1991);","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_1_22_4","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1111\/j.1469-1809.1995.tb01603.x","volume":"59","author":"Henske E. P.","year":"1995","unstructured":"Henske E. P., et al., Ann. Hum. Genet. 59, 25 (1995);","journal-title":"Ann. Hum. Genet."},{"key":"e_1_3_1_22_5","unstructured":"]. Exons identified in this manner were used to identify cDNA clones (i) by screening cDNA libraries by conventional methods (ii) by screening GenBank and dbEST databases and (iii) in reverse transcription PCR experiments. IMAGE clones were obtained from Research Genetics or the UK Human Genome Mapping Project (HGMP) Resource Centre."},{"key":"e_1_3_1_23_2","unstructured":"Complementary DNA selection was performed using the end-ligation coincident sequence cloning method ["},{"key":"e_1_3_1_23_3","doi-asserted-by":"crossref","first-page":"2011","DOI":"10.1093\/hmg\/3.11.2011","volume":"3","author":"Brookes A. J.","year":"1994","unstructured":"Brookes A. J., et al., Hum. Mol. Genet. 3, 2011 (1994);","journal-title":"Hum. Mol. Genet."},{"key":"e_1_3_1_23_4","unstructured":"]. A normalized infant brain cDNA library ["},{"key":"e_1_3_1_23_5","doi-asserted-by":"crossref","first-page":"9228","DOI":"10.1073\/pnas.91.20.9228","volume":"91","author":"Soares M. B.","year":"1994","unstructured":"Soares M. B., et al., Proc. Natl. Acad. Sci. U.S.A. 91, 9228 (1994);","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_1_23_6","unstructured":"] was screened using whole cosmids as probes. A human fetal brain cDNA library (Clontech) was screened by standard phage plating and filter lift methods."},{"key":"e_1_3_1_24_2","unstructured":"Cosmid (15) DNA was sheared and subcloned into M13mp18. Single clear plaques were picked using an automated picking device (PBA Technologies Cambridge UK) and expanded with JM101 and phage supernatant was collected. M13 DNA isolation was performed with the Sequatron robotic system ["},{"key":"e_1_3_1_24_3","doi-asserted-by":"publisher","DOI":"10.1126\/science.276.5320.1887"},{"key":"e_1_3_1_24_4","unstructured":"] following the solid-phase reversible immobilization protocol [T. L. Hawkins T. O\u2032Connor"},{"key":"e_1_3_1_24_5","doi-asserted-by":"crossref","first-page":"4543","DOI":"10.1093\/nar\/22.21.4543","volume":"22","author":"Roy A.","year":"1994","unstructured":"Roy A., Santillan C., Nucleic Acids Res. 22, 4543 (1994);","journal-title":"Nucleic Acids Res."},{"key":"e_1_3_1_24_6","unstructured":"]. Dye primer DNA sequencing used energy transfer primers and thermosequenase (Amersham) and electrophoresis was performed on Applied Biosystems 377 DNA sequencers. Gel files were extracted signal-processed and bases called with the program Trout (available from ) and were assembled with Alewife a sequence assembly package. Typically 1200 reads from a single cosmid assembled into one to three contigs which were then finished by directed primer walking and directed selection of reverse reads from existing M13 templates to span sequence gaps. All sequence data and protocols were available during the sequence process from our Web site ."},{"key":"e_1_3_1_25_2","unstructured":"Genomic sequence was analyzed with the program GRAIL2 to identify possible exons and gene models [Y. Xu R. Mural M. Shah E. Uberbacher Gene. Eng. Principles Methods 16 241 (1994)]. Putative transcriptional units were also identified by BLAST searches of public databases and comparison with our own collection of cDNA clones and exon trapping products."},{"key":"e_1_3_1_26_2","unstructured":"Oligonucleotide primers were designed to be external to exons by 40 to 60 bp where possible. DNA products with mobility shifts on heteroduplex analysis ["},{"key":"e_1_3_1_26_3","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1038\/ng0596-123","volume":"13","author":"Couch F. J.","year":"1996","unstructured":"Couch F. J., et al., Nature Genet. 13, 123 (1996);","journal-title":"Nature Genet."},{"key":"e_1_3_1_26_4","doi-asserted-by":"crossref","first-page":"10325","DOI":"10.1073\/pnas.90.21.10325","volume":"90","author":"Ganguly A.","year":"1993","unstructured":"Ganguly A., Rock M. J., Prockop D. J., Proc. Natl. Acad. Sci. U.S.A. 90, 10325 (1993);","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"e_1_3_1_26_5","unstructured":"] were subjected to sequence analysis of both strands."},{"key":"e_1_3_1_27_2","unstructured":"A transcriptional unit denoted B2 was identified from a brain cDNA library by hybridization with a cosmid near D9S1830 (22). A 4.5-kb cDNA clone was sequenced and contained no ORF. Database searches showed that this clone was the 3\u2032 portion of a 6.8-kb cDNA clone (KIAA0243) ["},{"key":"e_1_3_1_27_3","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1093\/dnares\/3.5.321","volume":"3","author":"Nagase T.","year":"1996","unstructured":"Nagase T., et al., DNA Res. 3, 321 (1996);","journal-title":"DNA Res."},{"key":"e_1_3_1_27_4","unstructured":"] which contained a 2.0-kb ORF. After the discovery of mutations in exon 15 of B2 5\u2032 RACE was performed with the Marathon cDNA kit (Clontech) using oligonucleotides derived from TSC1 cDNA clones or inferred by analysis of genomic sequence information (24). RACE and other cDNA clones were sequenced fully on both strands by means of Taq cycle sequencing methodology."},{"key":"e_1_3_1_28_2","doi-asserted-by":"crossref","unstructured":"R. F. Smith B. A. Wiese M. K. Wojzynski D. B. Davison K. C. Worley Genome Res. 6 454 (1996).","DOI":"10.1101\/gr.6.5.454"},{"key":"e_1_3_1_29_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.252.5009.1162"},{"key":"e_1_3_1_30_2","unstructured":"A BLAST search of the NCBI combined protein database using the TSC1 amino acid sequence gave the best match at a probability of 2.2 \u00d7 10 \u221218 with the  sequence with several regions of homology throughout the sequence but no areas of particularly strong match. The next lowest probability was 5.2 \u00d7 10 \u22128 ."},{"key":"e_1_3_1_31_2","unstructured":"Allele-specific amplification was performed on the renal cell carcinoma DNA using a primer specific for the normal allele not bearing the 2105delAAAG mutation. Sequence analysis of this product indicated that it contained the 1957delG mutation."},{"key":"e_1_3_1_32_2","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1111\/j.1469-1809.1994.tb01881.x","volume":"58","author":"Povey S.","year":"1994","unstructured":"Povey S., et al., Ann. Hum. Genet. 58, 107 (1994);","journal-title":"Ann. Hum. Genet."},{"key":"e_1_3_1_32_3","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1007\/BF00201608","volume":"94","author":"Janssen B.","year":"1994","unstructured":"Janssen B., et al., Hum. Genet. 94, 437 (1994).","journal-title":"Hum. Genet."},{"key":"e_1_3_1_33_2","doi-asserted-by":"crossref","first-page":"16409","DOI":"10.1074\/jbc.270.27.16409","volume":"270","author":"Wienecke R.","year":"1995","unstructured":"Wienecke R., Konig A., DeClue J. E., J. Biol. Chem. 270, 16409 (1995);","journal-title":"J. Biol. Chem."},{"key":"e_1_3_1_33_3","first-page":"6097","volume":"272","author":"Xiao G. H.","year":"1997","unstructured":"Xiao G. H., Shoarinejad F., Jin F., Golemis E. A., Yeung R. S., ibid. 272, 6097 (1997);","journal-title":"ibid."},{"key":"e_1_3_1_33_4","first-page":"913","volume":"13","author":"Wienecke R.","year":"1996","unstructured":"Wienecke R., et al., Oncogene 13, 913 (1996).","journal-title":"Oncogene"},{"key":"e_1_3_1_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/0888-7543(89)90129-8"},{"key":"e_1_3_1_35_2","unstructured":"We thank the hundreds of TSC patients and their families for blood samples and financial support (particularly V. Whittemore and W. Watts) and numerous clinicians (particularly A. Oranje H. Stroink M. Wildervanck de Blecourt H. Kros B. Prahl-Andersen and H. L. J. Tanghe) for assistance; H. Galjaard and P. Harper for support; R. Bakker S. Ramlakhan D. Humphrey Q. Wang M. Maheshwar A. L. W. Hesseling-Janssen N. Thomas and R. Slomski for technical support; and the UK HGMP Resource Centre and the European Collection of Animal Cell Cultures. Supported by the NIH National Tuberous Sclerosis Association Tuberous Sclerosis Association of Great Britain Dutch Organization for Scientific Research (NWO) Dutch Tuberous Sclerosis Association (STSN) Dutch Kidney Foundation Westminster Medical School Research Trust (Royds Fund) Bath Unit for Research into Paediatrics and New Zealand Health Resources Council."}],"container-title":["Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/science.277.5327.805","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,13]],"date-time":"2024-01-13T00:56:18Z","timestamp":1705107378000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/science.277.5327.805"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1997,8,8]]},"references-count":69,"journal-issue":{"issue":"5327","published-print":{"date-parts":[[1997,8,8]]}},"alternative-id":["10.1126\/science.277.5327.805"],"URL":"https:\/\/doi.org\/10.1126\/science.277.5327.805","relation":{},"ISSN":["0036-8075","1095-9203"],"issn-type":[{"value":"0036-8075","type":"print"},{"value":"1095-9203","type":"electronic"}],"subject":[],"published":{"date-parts":[[1997,8,8]]}}}