Identification and characterization of the tuberous sclerosis gene on chromosome 16
Abstract
Tuberous sclerosis (TSC) is an autosomal dominant multisystem disorder with loci assigned to chromosomes 9 and 16. Using pulsed-field gel electrophoresis (PFGE), we identified five TSC-associated deletions at 16p13.3. These were mapped to a 120 kb region that was cloned in cosmids and from which four genes were isolated. One gene, designated TSC2, was interrupted by all five PFGE deletions, and closer examination revealed several intragenic mutations, including one de novo deletion. In this case, Northern blot analysis identified a shortened transcript, while reduced expression was observed in another TSC family, confirming TSC2 as the chromosome 16 TSC gene. The 5.5 kb TSC2 transcript is widely expressed, and its protein product, tuberin, has a region of homology to the GTPase-activating protein GAP3.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
TSC is caused by a pathogenic variant in either TSC1 or TSC2.
“TSC is caused by a pathogenic variant in either TSC1 (coding for hamartin) located on chromosome 9q34 [23] or TSC2 (coding for tuberin) located on chromosome 16p13 [7].”
From Tuberous sclerosis complex is associated with a novel human tauopathy (2023) · cites this paper as [7]
Cites
The neurofibromatosis type 1 gene encodes a protein related to GAP
Xu, G., O'Connell, P., Viskochil, D., Cawthon, R., Robertson, M., Culver, M., Dunn, D., Stevens, J., Gesteland, R., White, R., et al. (1990) · Cell · doi:10.1016/0092-8674(90)90024-9 · Cited by 1,095 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling
Inoki, K., Li, Y., Zhu, T., Wu, J., & Guan, K.-L. (2002) · Nature Cell Biology · doi:10.1038/ncb839 · Cited by 3,083 · see citing works
Strong association of de novo copy number mutations with autism
Sebat, J., Lakshmi, B., Malhotra, D., Troge, J., Lese-Martin, C., Walsh, T., Yamrom, B., Yoon, S., Krasnitz, A., Kendall, J., et al. (2007) · Science · doi:10.1126/science.1138659 · Cited by 2,795 · see citing works
DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources
Firth, H. V., Richards, S. M., Bevan, A. P., Clayton, S., Corpas, M., Rajan, D., Vooren, S. V., Moreau, Y., Pettett, R. M., & Carter, N. P. (2009) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2009.03.010 · Cited by 1,990 · see citing works
Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling
Inoki, K., Li, Y., Xu, T., & Guan, K.-L. (2003) · Genes & Development · doi:10.1101/gad.1110003 · Cited by 1,911 · see citing works
The Tuberous Sclerosis Complex
Crino, P. B., Nathanson, K. L., & Henske, E. P. (2006) · New England Journal of Medicine · doi:10.1056/nejmra055323 · Cited by 1,793 · see citing works
Identification of the Tuberous Sclerosis Gene <i>TSC1</i> on Chromosome 9q34
Slegtenhorst, M. V., Hoogt, R. D., Hermans, C., Nellist, M., Janssen, B., Verhoef, S., Lindhout, D., Ouweland, A. V. D., Halley, D., Young, J., et al. (1997) · Science · doi:10.1126/science.277.5327.805 · Cited by 1,648 · see citing works
The TSC1–TSC2 complex: a molecular switchboard controlling cell growth
Huang, J., & Manning, B. D. (2008) · Biochemical Journal · doi:10.1042/bj20080281 · Cited by 1,237 · see citing works
Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis
Ehninger, D., Han, S., Shilyansky, C., Zhou, Y., Li, W., Kwiatkowski, D. J., Ramesh, V., & Silva, A. J. (2008) · Nature Medicine · doi:10.1038/nm1788 · Cited by 879 · see citing works
Regulation of mTORC1 by amino acids
Bar-Peled, L., & Sabatini, D. M. (2014) · Trends in Cell Biology · doi:10.1016/j.tcb.2014.03.003 · Cited by 773 · see citing works
Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway
Polivka, J., & Janku, F. (2014) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.12.004 · Cited by 765 · see citing works
Chen, C., Liu, Y., Liu, R., Ikenoue, T., Guan, K.-L., Liu, Y., & Zheng, P. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20081297 · Cited by 682 · see citing works
Recent advances in genetics, diagnosis, localization, and treatment of pheochromocytoma
Pacak, K., Linehan, W. M., Eisenhofer, G., Walther, M. M., & Goldstein, D. S. (2001) · Annals of Internal Medicine · doi:10.7326/0003-4819-134-4-200102200-00016 · Cited by 618 · see citing works
Somatic mutation, genomic variation, and neurological disease
Poduri, A., Evrony, G. D., Cai, X., & Walsh, C. A. (2013) · Science · doi:10.1126/science.1237758 · Cited by 584 · see citing works
Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products
van Slegtenhorst, M. (1998) · Human Molecular Genetics · doi:10.1093/hmg/7.6.1053 · Cited by 565 · see citing works
TSC2 regulates VEGF through mTOR-dependent and -independent pathways
Brugarolas, J. B., Vazquez, F., Reddy, A., Sellers, W. R., & Kaelin, W. G. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00187-9 · Cited by 528 · see citing works
Amino acids and mTORC1: from lysosomes to disease
Efeyan, A., Zoncu, R., & Sabatini, D. M. (2012) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2012.05.007 · Cited by 436 · see citing works
Bucan, M., Abrahams, B. S., Wang, K., Glessner, J. T., Herman, E. I., Sonnenblick, L. I., Alvarez Retuerto, A. I., Imielinski, M., Hadley, D., Bradfield, J. P., et al. (2009) · PLoS Genetics · doi:10.1371/journal.pgen.1000536 · Cited by 424 · see citing works
Uhlmann, E. J., Wong, M., Baldwin, R. L., Bajenaru, M. L., Onda, H., Kwiatkowski, D. J., Yamada, K., & Gutmann, D. H. (2002) · Annals of Neurology · doi:10.1002/ana.10283 · Cited by 372 · see citing works
Jansen, L. A., Mirzaa, G. M., Ishak, G. E., O'Roak, B. J., Hiatt, J. B., Roden, W. H., Gunter, S. A., Christian, S. L., Collins, S., Adams, C., et al. (2015) · Brain · doi:10.1093/brain/awv045 · Cited by 364 · see citing works
Activity of TSC2 is inhibited by AKT-mediated phosphorylation and membrane partitioning
Cai, S.-L., Tee, A. R., Short, J. D., Bergeron, J. M., Kim, J., Shen, J., Guo, R., Johnson, C. L., Kiguchi, K., & Walker, C. L. (2006) · The Journal of Cell Biology · doi:10.1083/jcb.200507119 · Cited by 359 · see citing works
A unified genetic theory for sporadic and inherited autism
Zhao, X., Leotta, A., Kustanovich, V., Lajonchere, C., Geschwind, D. H., Law, K., Law, P., Qiu, S., Lord, C., Sebat, J., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0705803104 · Cited by 319 · see citing works
McConnell, M. J., Moran, J. V., Abyzov, A., Akbarian, S., Bae, T., Cortes-Ciriano, I., Erwin, J. A., Fasching, L., Flasch, D. A., Freed, D., et al. (2017) · Science · doi:10.1126/science.aal1641 · Cited by 262 · see citing works
Protein interactome reveals converging molecular pathways among autism disorders
Sakai, Y., Shaw, C. A., Dawson, B. C., Dugas, D. V., Al-Mohtaseb, Z., Hill, D. E., & Zoghbi, H. Y. (2011) · Science Translational Medicine · doi:10.1126/scitranslmed.3002166 · Cited by 226 · see citing works
Neuropathology of tuberous sclerosis
Mizuguchi, M., & Takashima, S. (2001) · Brain and Development · doi:10.1016/s0387-7604(01)00304-7 · Cited by 205 · see citing works
Reversing Neurodevelopmental Disorders in Adults
Ehninger, D., Li, W., Fox, K., Stryker, M. P., & Silva, A. J. (2008) · Neuron · doi:10.1016/j.neuron.2008.12.007 · Cited by 196 · see citing works
Biallelic <i>TSC</i> gene inactivation in tuberous sclerosis complex
Crino, P. B., Aronica, E., Baltuch, G., & Nathanson, K. L. (2010) · Neurology · doi:10.1212/wnl.0b013e3181e04325 · Cited by 153 · see citing works
Sestan, N., & State, M. W. (2018) · Neuron · doi:10.1016/j.neuron.2018.10.015 · Cited by 127 · see citing works
Boer, K., Crino, P. B., Gorter, J. A., Nellist, M., Jansen, F. E., Spliet, W. G. M., Van Rijen, P. C., Wittink, F. R. A., Breit, T. M., Troost, D., et al. (2010) · Brain Pathology · doi:10.1111/j.1750-3639.2009.00341.x · Cited by 148 · see citing works
Veenstra-VanderWeele, J., & Blakely, R. D. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2011.185 · Cited by 128 · see citing works
Ehninger, D., De Vries, P. J., & Silva, A. J. (2009) · Journal of Intellectual Disability Research · doi:10.1111/j.1365-2788.2009.01208.x · Cited by 120 · see citing works
The efficacy and safety of low-dose sirolimus for treatment of lymphangioleiomyomatosis
Ando, K., Kurihara, M., Kataoka, H., Ueyama, M., Togo, S., Sato, T., Doi, T., Iwakami, S.-I., Takahashi, K., Seyama, K., et al. (2013) · Respiratory Investigation · doi:10.1016/j.resinv.2013.03.002 · Cited by 106 · see citing works
Cellular and synaptic network defects in autism
Peça, J., & Feng, G. (2012) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2012.02.015 · Cited by 96 · see citing works
Li, M., Zhou, Y., Chen, C., Yang, T., Zhou, S., Chen, S., Wu, Y., & Cui, Y. (2019) · Orphanet Journal of Rare Diseases · doi:10.1186/s13023-019-1012-x · Cited by 83 · see citing works
Lauritsen, M. B., Als, T. D., Dahl, H. A., Flint, T. J., Wang, A. G., Vang, M., Kruse, T. A., Ewald, H., & Mors, O. (2006) · Molecular Psychiatry · doi:10.1038/sj.mp.4001754 · Cited by 82 · see citing works
Sarnat, H. B., & Flores-Sarnat, L. (2015) · Brain and Development · doi:10.1016/j.braindev.2014.08.010 · Cited by 73 · see citing works
Walsh, K. M., & Bracken, M. B. (2011) · Genetics in Medicine · doi:10.1097/gim.0b013e3182076c0c · Cited by 65 · see citing works
Loss of the tuberous sclerosis complex protein tuberin causes Purkinje cell degeneration
Reith, R. M., Way, S., McKenna, J., Haines, K., & Gambello, M. J. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.02.014 · Cited by 65 · see citing works
Newborn cortical neurons: only for neonates?
Feliciano, D. M., & Bordey, A. (2013) · Trends in Neurosciences · doi:10.1016/j.tins.2012.09.004 · Cited by 51 · see citing works
Lee, W. S., Baldassari, S., Stephenson, S. E. M., Lockhart, P. J., Baulac, S., & Leventer, R. J. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23031344 · Cited by 45 · see citing works
Mozaffari, M., Hoogeveen-Westerveld, M., Kwiatkowski, D., Sampson, J., Ekong, R., Povey, S., den Dunnen, J. T., van den Ouweland, A., Halley, D., & Nellist, M. (2009) · BMC Medical Genetics · doi:10.1186/1471-2350-10-88 · Cited by 36 · see citing works
Zech, R., Kiontke, S., Mueller, U., Oeckinghaus, A., & Kümmel, D. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.732446 · Cited by 29 · see citing works
Analysis of TSC1 truncations defines regions involved in TSC1 stability, aggregation and interaction
Hoogeveen-Westerveld, M., Exalto, C., Maat-Kievit, A., van den Ouweland, A., Halley, D., & Nellist, M. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2010.06.004 · Cited by 25 · see citing works
The TSC1-TSC2 complex consists of multiple TSC1 and TSC2 subunits
Hoogeveen-Westerveld, M., van Unen, L., van den Ouweland, A., Halley, D., Hoogeveen, A., & Nellist, M. (2012) · BMC Biochemistry · doi:10.1186/1471-2091-13-18 · Cited by 24 · see citing works
Tuberous sclerosis complex is associated with a novel human tauopathy
Hwang, J.-H. L., Perloff, O. S., Gaus, S. E., Benitez, C., Alquezar, C., Cosme, C. Q., Nana, A. L., Vatsavayai, S. C., Ramos, E. M., Geschwind, D. H., et al. (2023) · Acta Neuropathologica · doi:10.1007/s00401-022-02521-5 · Cited by 15 · see citing works
Deciduous teeth in tuberous sclerosis
Russell, B. G., Russell, M. B., Praetorius, F., & Russell, C. A. (1996) · Clinical Genetics · doi:10.1111/j.1399-0004.1996.tb02343.x · Cited by 9 · see citing works
Zhang, J., Argueta, D., Tong, X., Vinters, H. V., Mathern, G. W., & Cepeda, C. (2025) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2024.1486315 · Cited by 3 · see citing works
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 1993-12
- Volume
- 75
- Issue
- 7
- Pages
- 1305-1315
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2235106477
- Cited by
- 1,645
- References
- 1
- Citations by year
- 2026: 7 · 2025: 32 · 2024: 35 · 2023: 35 · 2022: 50 · 2021: 52 · 2020: 39 · 2019: 36 · 2018: 54 · 2017: 57 · 2016: 51 · 2015: 53 · 2014: 50 · 2013: 57 · 2012: 59
- FWCI
- 20.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Funders
- Wellcome Trust
- Topics
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and rare skin diseases.
- Keywords
- tuberous sclerosis complex, TSC2 gene, tuberin, chromosome 16p13.3, gene mapping, intragenic mutations, de novo deletion, GTPase-activating protein, autosomal dominant disorder
- MeSH terms
- Amino Acid Sequence, Base Sequence, Chromosomes, Human, Pair 16, Cloning, Molecular, Genes, Genes, Dominant, Humans, Molecular Sequence Data, RNA, Messenger, Tuberous Sclerosis, Gene Expression, Sequence Alignment, Sequence Deletion, Sequence Homology, Amino Acid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
