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The neurobiology of the tuberous sclerosis complex

NeuroMolecular Medicine volume 8, pages 531–546 (2006)Cite this article

Abstract

Tuberous sclerosis complex (TSC) is a multisystem disorder that affects numerous organ systems. Brain lesions that form during development, known as tubers, are highly associated with epilepsy, cognitive disability, and autism. Following the identification of two genes and their encoded proteins, TSC1 (hamartin) and TSC2 (tuberin), responsible for TSC, identification of several downstream protein cascades that might be affected in TSC have been discovered. Of primary importance is the mammalian target of rapamycin pathway that controls cell growth and protein synthesis. The mechanisms governing brain lesion growth have not been fully identified but likely altered regulation of the mammalian target of rapamycin cascade by hamartin and tuberin during development leads to aberrant cell growth. Secondary effects of TSC gene mutations might disrupt normal neuronal migration and cerebral cortical lamination. Numerous studies have identified changes in gene and protein expression in animal models of TSC and in human TSC brain specimens that contribute to altered brain cytoarchitecture. This review will provide an overview of the neurobiological aspects of TSC.

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References

  • Astridinis A. and Henske E. P. (2005) Tuberous sclerosis complex: linking growth and energy signaling pathways with human disease. Oncogene 24, 7475–7481.

    Google Scholar 

  • Astrinidis A., Senapedis W., Coleman T. R., and Henske E. P. (2003) Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin B. J. Biol. Chem. 278, 51,372–51,379.

    CAS  Google Scholar 

  • Baron Y. and Barkovich A. J. (1999) MR imaging of tuberous sclerosis in neonates and young infants. AJNR Am. J. Neuroradiol. 20, 907–916.

    PubMed  CAS  Google Scholar 

  • Baybis M., Yu J., Lee A., et al. (2004) mTOR Cascade Activation Distinguishes Tubers from Focal Cortical Dysplasia. Ann. Neurol. 56, 478–487.

    PubMed  CAS  Google Scholar 

  • Birchenall-Roberts M. C., Fu T., Bang O. S., et al. (2004) Tuberous Sclerosis Complex 2 Gene Product Interacts with Human SMAD Proteins: a molecular link of two tumor suppressor pathways. J. Biol. Chem. 279, 25,605–25,613.

    CAS  Google Scholar 

  • Carlson B. A., Houser O. W., and Gomez M. R. (1999) Brain Imaging in the Tuberous Sclerosis Complex, in Tuberous Sclerosis Complex: developmental Perspectives in Psychiatry, Gomez M. R., Sampson J. R., and Whittemore V. H., eds., Oxford University Press, New York, pp. 85–100.

    Google Scholar 

  • Catania M. G., Mischel P. S., and Vinters H. V. (2001) Hamartin and tuberin interaction with the G2/M cyclin-dependent kinase CDK1 and its regulatory cyclins A and B. J. Neuropathol. Exp. Neurol. 60, 711–723.

    PubMed  CAS  Google Scholar 

  • Chan J. A., Zhang H., Roberts P. S., et al. (2004) Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J. Neuropathol. Exp. Neurol. 63, 1236–1242.

    PubMed  CAS  Google Scholar 

  • Chugani D. C., Chugani H. T., Muzik O., et al. (1998) Imaging epileptogenic tubers in children with tuberous sclerosis complex using alpha-[11C]methyl-L-tryptophan positron emission tomography. Ann. Neurol. 44, 858–866.

    PubMed  CAS  Google Scholar 

  • Consortium ECTS (1993) Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75, 1305–1315.

    Google Scholar 

  • Crino P. B. and Henske E. P. (1999) New developments in the neurobiology of the tuberous sclerosis complex. Neurology. 53, 1384–1390.

    PubMed  CAS  Google Scholar 

  • Crino P. B., Miyata H., and Vinters H. V. (2002) Neurodevelopmental Disorders as a Cause of Seizures: Neuropathologic, Genetic, and Mechanistic Considerations. Brain Pathol. 12, 212–233.

    PubMed  CAS  Article  Google Scholar 

  • Crino P. B., Trojanowski J. Q., Dichter M. A., and Eberwine J. (1996) Embryonic neuronal markers in tuberous sclerosis: single-cell molecular pathology. Proc. Natl. Acad. Sci. USA 93, 14,152–14,157.

    CAS  Google Scholar 

  • Curatolo P., Bombardieri R., Verdecchia M., and Seri S. (2005) Intractable Seizures in Tuberous Sclerosis Complex: From Molecular Pathogenesis to the Rationale for Treatment. J. Child Neurol. 20, 318–325.

    PubMed  Google Scholar 

  • Curatolo P., Seri S., Verdecchia M., and Bombardieri R. (2001) Infantile spasms in tuberous sclerosis complex. Brain Dev. 23, 502–507.

    PubMed  CAS  Google Scholar 

  • Dabora S. L., Jozwiak S., Franz D. N., et al. (2001) Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs. Am. J. Hum. Genet. 68, 64–80.

    PubMed  CAS  Google Scholar 

  • Dan H. C., Sun M., Yang L., et al. (2002) Phosphatidylinositol 3-kinase/Akt pathway regulates tuberous sclerosis tumor suppressor complex by phosphorylation of tuberin. J. Biol. Chem. 277, 35,364–35,370.

    CAS  Google Scholar 

  • DiMario F. J. Jr. (2004) Brain abnormalities in tuberous sclerosis complex. J. Child Neurol. 19, 650–657.

    PubMed  Google Scholar 

  • Ess K. C., Kamp C. A., Tu B. P., and Gutmann D. H. (2005) Developmental origin of subependymal giant cell astrocytoma in tuberous sclerosis complex. Neurology. 64, 1446–1449.

    PubMed  Google Scholar 

  • Ess K. C., Uhlmann E. J., Li W., et al. (2004) Expression profiling in tuberous sclerosis complex (TSC) knockout mouse astrocytes to characterize human TSC brain pathology. Glia 46, 28–40.

    PubMed  Google Scholar 

  • Fauser S., Becker A., Schulze-Bonhage A., et al. (2004) CD34-immunoreactive balloon cells in cortical malformations. Acta Neuropathol. (Berl.) 108, 272–278.

    Google Scholar 

  • Finlay G. A., York B., Karas R. H., et al. (2004) Estrogen-induced smooth muscle cell growth is regulated by tuberin and associated with altered activation of platelet-derived growth factor receptor-beta and ERK-1/2. J. Biol. Chem. 279, 23,114–23,122.

    CAS  Google Scholar 

  • Gao X. and Pan D. (2001) TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes Dev. 15, 1383–1392.

    PubMed  CAS  Google Scholar 

  • Gao X., Zhang Y., Arrazola P., et al. (2002) Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat. Cell Biol. 4, 699–704.

    PubMed  CAS  Google Scholar 

  • Goh S., Butler W., and Thiele E. A. (2004) Subependymal giant cell tumors in tuberous sclerosis complex. Neurology 63, 1457–1461.

    PubMed  Google Scholar 

  • Goh S., Kwiatkowski D. J., Dorer D. J., and Thiele E. A. (2005) Infantile spasms and intellectual outcomes in children with tuberous sclerosis complex. Neurology 65, 235–238.

    PubMed  Google Scholar 

  • Gomez M. R. (1999) Natural History of Cerebral Tuberous Sclerosis, in Tuberous Sclerosis Complex: Developmental Perspectives in Psychiatry, Gomez M. R., Sampson J. R., and Whittemore V. H., eds., Oxford University Press, New York, pp. 29–46.

    Google Scholar 

  • Goodman M., Lamm S. H., Engel A., Shepherd C. W., Houser O. W., and Gomez M. R. (1997) Cortical tuber count: a biomarker indicating neurologic severity of tuberous sclerosis complex. J. Child Neurol. 12, 85–90.

    PubMed  CAS  Google Scholar 

  • Griffiths P. D., Bolton P., and Verity C. (1998) White matter abnormalities in tuberous sclerosis complex. Acta Radiol. 39, 482–486.

    PubMed  CAS  Google Scholar 

  • Gutmann D. H., Zhang Y., Hasbani M. J., Goldberg M. P., Plank T. L., and Henske E. P. (2000) Expression of the tuberous sclerosis complex gene products, hamartin and tuberin, in central nervous system tissues. Acta Neuropathol. (Berl.) 99, 223–230.

    CAS  Google Scholar 

  • Haddad L. A., Smith N., Bowser M., et al. (2002) The TSC1 tumor suppressor hamartin interacts with neurofilament-L and possibly functions as a novel integrator of the neuronal cytoskeleton. J. Biol. Chem. 277, 44,180–44,186.

    CAS  Google Scholar 

  • Henske E. P., Scheithauer B. W., Short M. P., et al. (1996) Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. Am. J. Hum. Genet. 59, 400–406.

    PubMed  CAS  Google Scholar 

  • Henske E. P., Wessner L. L., Golden J., et al. (1997) Loss of tuberin in both subependymal giant cell astrocytomas and angiomyolipomas supports a two-hit model for the pathogenesis of tuberous sclerosis tumors. Am. J. Pathol. 151, 1639–1647.

    PubMed  CAS  Google Scholar 

  • Hirose T., Scheithauer B. W., Lopes M. B., et al. (1995) Tuber and subependymal giant cell astrocytoma associated with tuberous sclerosis: an immunohistochemical, ultrastructural, and immunoelectron and microscopic study. Acta Neuropathol. (Berl.) 90, 387–399.

    CAS  Google Scholar 

  • Hosoya M., Naito H., and Nihei K. (1999) Neurological prognosis correlated with variations over time in the number of subependymal nodules in tuberous sclerosis. Brain Dev. 21, 544–547.

    PubMed  CAS  Google Scholar 

  • Humphreys R. P. (2004) The modernization of pediatric neurosurgery. The Donald D. Matson Lecture 2003. Childs Nerv. Syst. 20, 18–22.

    PubMed  Google Scholar 

  • Im E., von Lintig F. C., Chen J., et al. (2002) Rheb is in a high activation state and inhibits B-Raf kinase in mammalian cells. Oncogene 21, 6356–6365.

    PubMed  CAS  Google Scholar 

  • Jansen L. A., Uhlmann E. J., Crino P. B., Gutmann D. H., and Wong M. (2005) Epileptogenesis and Reduced Inward Rectifier Potassium Current in Tuberous Sclerosis Complex-1-Deficient Astrocytes. Epilepsia 46, 1871–1880.

    PubMed  CAS  Google Scholar 

  • Johnson M. W., Emelin J. K., Park S. H., and Vinters H. (1999) Co-localization of TSC1 and TSC2 gene products in tubers of patients with tuberous sclerosis. Brain Pathol. 9, 45–54.

    PubMed  CAS  Article  Google Scholar 

  • Johnson M. W., Kerfoot C., Bushnell T., Li M., and Vinters H. V. (2001) Hamartin and tuberin expression in human tissues. Mod. Pathol: Official J. US and Can. Acad. Pathol., Inc. 14, 202–210.

    CAS  Google Scholar 

  • Joinson C., O'Callaghan F. J., Osborne J. P., Martyn C., Harris T., and Bolton P. F. (2003) Learning disability and epilepsy in an epidemiological sample of individuals with tuberous sclerosis complex. Psychol. Med. 33, 335–344.

    PubMed  CAS  Google Scholar 

  • Jones A. C., Daniells C. E., Snell R. G., et al. (1997) Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis. Hum. Mol. Genet. 6, 2155–2161.

    PubMed  CAS  Google Scholar 

  • Jones A. C., Shyamsundar M. M., Thomas M. W., et al. (1999) Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. Am. J. Hum. Genet. 64, 1305–1315.

    PubMed  CAS  Google Scholar 

  • Kerfoot C., Wienecke R., Menchine M., et al. (1996) Localization of tuberous sclerosis 2 mRNA and its protein product tuberin in normal human brain and in cerebral lesion of patients with tuberous sclerosis. Brain Pathol. 6, 367–377.

    PubMed  CAS  Google Scholar 

  • Kim S. K., Wang K. C., Cho B. K., et al. (2001) Biological behavior and tumorigenesis of subependymal giant cell astrocytomas. J. Neuro-Oncol. 52, 217–225.

    CAS  Google Scholar 

  • Knudson A. (1971) Mutation and cancer: statistical study of retinoblastoma. Proc. Natl. Acad. Sci. USA 68, 820–823.

    PubMed  Google Scholar 

  • Koh S., Jayakar P., Dunoyer C., et al. (2000) Epilepsy surgery in children with tuberous sclerosis complex: presurgical evaluation and outcome. Epilepsia 41, 1206–1213.

    PubMed  CAS  Google Scholar 

  • Kwiatkowska J., Wigowska-Sowinska J., Napierala D., Slomski R., and Kwiatkowski D. J. (1999) Mosaicism in tuberous sclerosis as a potential cause of the failure of molecular diagnosis. N. Engl. J. Med. 340, 703–707.

    PubMed  CAS  Google Scholar 

  • Kyin R., Hua Y., Baybis M., et al. (2001) Differential cellular expression of neurotrophins in cortical tubers of the tuberous sclerosis complex. Am. J. Pathol. 159, 1541–1554.

    PubMed  CAS  Google Scholar 

  • Lamb R. F., Roy C., Diefenbach T. J., et al. (2000) The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho. Nat. Cell Biol. 2, 281–287.

    PubMed  CAS  Google Scholar 

  • Lazarowski A., Lubieniecki F., Camarero S., et al. (2004) Multidrug resistance proteins in tuberous sclerosis and refractory epilepsy. Pediatr. Neurol. 30, 102–106.

    PubMed  Google Scholar 

  • Lee A., Maldonado M., Baybis M., et al. (2003) Markers of cellular proliferation are expressed in cortical tubers. Ann. Neurol. 53, 668–673.

    PubMed  CAS  Google Scholar 

  • Li Y., Inoki K., Vacratsis P., and Guan K. L. (2003) The p38 and MK2 kinase cascade phosphorylates tuberin, the tuberous sclerosis 2 gene product, and enhances its interaction with 14-3-3. J. Biol. Chem. 278, 13,663–13,667.

    CAS  Google Scholar 

  • Lopes M. B., Altermatt H. J., Scheithauer B. W., Shepherd C. W., and VandenBerg S. R. (1996) Immunohistochemical characterization of subependymal giant cell astrocytomas. Acta Neuropathol. (Berl.) 91, 368–375.

    CAS  Google Scholar 

  • Lou D., Griffith N., and Noonan D. J. (2001) The tuberous sclerosis 2 gene product can localize to nuclei in a phosphorylation-dependent manner. Mol. Cell Biol. Res. Commun. 4, 374–380.

    PubMed  CAS  Google Scholar 

  • Ma L., Chen Z., Erdjument-Bromage H., Tempst P., and Pandolfi P. P. (2005) Phosphorylation and functional inactivation of TSC2 by Erk implications for tuberous sclerosis and cancer pathogenesis. Cell 121, 179–193.

    PubMed  CAS  Google Scholar 

  • Maheshwar M. M., Cheadle J. P., Jones A. C., et al. (1997) The GAP-related domain of tuberin, the product of the TSC2 gene, is a target for missense mutations in tuberous sclerosis. Hum. Mol. Genet. 6, 1991–1996.

    PubMed  CAS  Google Scholar 

  • Maldonado M., Baybis M., Newman D., et al. (2003) Expression of ICAM-1, TNF-alpha, NF kappa B, and MAP kinase in tubers of the tuberous sclerosis complex. Neurobiol. dis. 14, 279–290.

    PubMed  CAS  Google Scholar 

  • Manning B. D., Tee A. R., Logsdon M. N., Blenis J., and Cantley L. C. (2003) Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol. Cell Biol. 10, 151–162.

    Google Scholar 

  • Manning B. D., Logsdon M. N., Lipovsky A. I., Abbott D., Kwiatkowski D. J., and Cantley L. C. (2005) Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2. Genes Dev. 19, 1773–1778.

    PubMed  CAS  Google Scholar 

  • Miyata H., Chiang A. C., and Vinters H. V. (2004) Insulin signaling pathways in cortical dysplasia and TSCtubers: tissue microarray analysis. Ann. Neurol. 56, 510–509.

    PubMed  CAS  Google Scholar 

  • Mizuguchi M. and Takashima S. (2001) Neuropathology of tuberous sclerosis. Brain Dev. 23, 508–515.

    PubMed  CAS  Google Scholar 

  • Murthy V., Han S., Beauchamp R. L., et al. (2004) Pam and its ortholog highwire interact with and may negatively regulate the TSC1.TSC2 complex. J. Biol. Chem. 279, 1351–1358.

    PubMed  CAS  Google Scholar 

  • Murthy V., Stemmer-Rachamimov A. O., Haddad L. A., et al. (2001) Developmental expression of the tuberous sclerosis proteins tuberin and hamartin. Acta Neuropathol. (Berl.) 101, 202–210.

    CAS  Google Scholar 

  • Niida Y., Lawrence-Smith N., Banwell A., et al. (1999) Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated patients with tuberous sclerosis. Hum. Mutat. 14, 412–422.

    PubMed  CAS  Google Scholar 

  • Niida Y., Stemmer-Rachamimov A. O., Logrip M., et al. (2001) Survey of somatic mutations in tuberous sclerosis complex (TSC) hamartomas suggests different genetic mechanisms for pathogenesis of TSC lesions. Am. J. Hum. Genet. 69, 493–503.

    PubMed  CAS  Google Scholar 

  • Noonan D. J., Lou D., Griffith N., and Vanaman T. C. (2002) A calmodulin binding site in the tuberous sclerosis 2 gene product is essential for regulation of transcription events and is altered by mutations linked to tuberous sclerosis and lymphangioleiomyomatosis. Arch. Biochem. Biophys. 398, 132–140.

    PubMed  CAS  Google Scholar 

  • O'Callaghan F. J., Harris T., Joinson C., et al. (2004) The relation of infantile spasms, tubers, and intelligence in tuberous sclerosis complex. Arch. Dis. Child. 89, 530–533.

    PubMed  Google Scholar 

  • Onda H., Crino P. B., Zhang H., et al. (2002) Tsc2 null murine neuronal epithelial cells are a model for human tuber giant cells, and show activation of an mTOR pathway. Mol. Cell Neurosci. 21, 561–574.

    PubMed  CAS  Google Scholar 

  • Park S. H., Pepkowitz S. H., Kerfoot C., et al. (1997) Tuberous sclerosis in a 20-week gestation fetus: immunohistochemical study. Acta Neuropathol. (Berl.) 94, 180–186.

    CAS  Google Scholar 

  • Plank T. L., Yeung R. S., and Henske E. P. (1998) Hamartin, the product of the tuberous sclerosis 1 (TSC1) gene, interacts with tuberin and appears to be localized to cytoplasmic vesicles. Cancer Res. 58, 4766–4770.

    PubMed  CAS  Google Scholar 

  • Plank T. L., Logginidou H., Klein-Szanto A., and Henske E. P. (1999) The expression of hamartin, the product of the TSC1 gene, in normal human tissues and in TSC1- and TSC2-linked angiomyolipomas. Mod. Pathol. 12, 539–545.

    PubMed  CAS  Google Scholar 

  • Potter C. J., Huang H., and Xu T. (2001) Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell 105, 357–368.

    PubMed  CAS  Google Scholar 

  • Prather P. and de Vries P. J. (2004) Behavioral and cognitive aspects of tuberous sclerosis complex. J. Child Neurol. 19, 666–674.

    PubMed  Google Scholar 

  • Ridler K., Bullmore E. T., De Vries P. J., et al. (2001) Widespread anatomical abnormalities of grey and white matter structure in tuberous sclerosis. Psychol. Med. 31, 1437–1446.

    PubMed  CAS  Article  Google Scholar 

  • Roach E. S., Gomez M. R., and Northrup H. (1998) Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J. Child Neurol. 13, 624–628.

    PubMed  CAS  Article  Google Scholar 

  • Rosner M. and Hengstschlager M. (2004) Tuberin binds p27 and negatively regulates its interaction with the SCF component Skp2. J. Biol. Chem. 79, 48,707–48,715.

    Google Scholar 

  • Rott H. D., Lemcke B., Zenker M., Huk W., Horst J., and Mayer K. (2002) Cyst-like cerebral lesions in tuberous sclerosis. Am. J. Med. Genet. 111, 435–439.

    PubMed  Google Scholar 

  • Roux P. P., Ballif B. A., Anjum R., Gygi S. P., and Blenis J. (2004) Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase. Proc. Natl. Acad. Sci. USA 101, 13,489–13,494.

    CAS  Google Scholar 

  • Sancak O., Nellist M., Goedbloed M., et al. (2005) Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype-phenotype correlations and comparison of diagnostic DNA techniques in Tuberous Sclerosis Complex. Eur. J. Hum. Genet. 13, 731–741.

    PubMed  CAS  Google Scholar 

  • Saucedo L. J., Gao X., Chiarelli D. A., Li L., Pan D., and Edgar B. A. (2003) Rheb promotes cell growth as a component of the insulin/TOR signalling network. Nat. Cell Biol. 5, 566–571.

    PubMed  CAS  Google Scholar 

  • Scheithauer B. W. and Reagan T. J. (1999) Neuropathology, in Tuberous Sclerosis Complex: Developmental Perspectives in Psychiatry, Gomez M. R., Sampson J. R., and Whittemore V. H., eds., Oxford University Press, New York, pp. 101–144.

    Google Scholar 

  • Sharma M. C., Ralte A. M., Gaekwad S., Santosh V., Shankar S. K., and Sarkar C. (2004) Subependymal Giant Cell Astrocytoma-a Clinicopathological Study of 23 Cases with Special Emphasis on Histogenesis. Pathol. Oncol. Res. 10, 219–224.

    PubMed  Article  Google Scholar 

  • Shumway S. D., Li Y., and Xiong Y. (2003) 14-3-3beta binds to and negatively regulates the tuberous sclerosis complex 2 (TSC2) tumor suppressor gene product, tuberin. J. Biol. Chem. 278, 2089–2092.

    PubMed  CAS  Google Scholar 

  • Smalley S. L. (1997) Autism and tuberous sclerosis. J. Autism Dev. Disord. 28, 407–414.

    Google Scholar 

  • Stefansson K., Wollmann R. L., and Huttenlocher P. R. (1999) Lineages of Cells in the Central Nervous System, in Tuberous Sclerosis Complex: Developmental Perspectives in Psychiatry, Gomez M. R., Sampson J. R., Whittemore V. H., eds., Oxford University Press: New York, pp. 250–262.

    Google Scholar 

  • Stocker H., Radimerski T., Schindelholz B., et al. (2003) Rheb is an essential regulator of S6K in controlling cell growth in Drosophila. Nat. Cell Biol. 5, 559–566.

    PubMed  CAS  Google Scholar 

  • Takahashi D. K., Dinday M. T., Barbaro N. M., and Baraban S. C. (2004) Abnormal cortical cells and astrocytomas in the Eker rat model of tuberous sclerosis complex. Epilepsia 45, 1525–1530.

    PubMed  Google Scholar 

  • Tavazoie S. F., Alvarez V. A., Ridenour D. A., Kwiatkowski D. J., and Sabatini B. L. (2005) Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat. Neurosci. 8, 1727–1734.

    PubMed  CAS  Google Scholar 

  • Tee A. R., Manning B. D., Roux P. P., Cantley L. C., and Blenis J. (2003) Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb. Curr. Biol. 13, 1259–1268.

    PubMed  CAS  Google Scholar 

  • Thiele E. A. (2004) Managing epilepsy in tuberous sclerosis complex. J. Child Neurol. 19, 680–686.

    PubMed  Google Scholar 

  • Uhlmann E. J., Wong M., Baldwin R. L., et al. (2002) Astrocyte-Specific TSC1 Conditional Knockout Mice Exhibit Abnormal Neuronal Organization and Seizures. Ann. Neurol. 52, 285–296.

    PubMed  CAS  Google Scholar 

  • van Slegtenhorst M. and de Hoogt R. (1997) Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277, 805–808.

    PubMed  Google Scholar 

  • van Slegtenhorst M., Nellist M., Nagelkerken B., et al. (1998) Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum. Mol. Genet. 7, 1053–1057.

    PubMed  Google Scholar 

  • van Slegtenhorst M., Verhoef S., Tempelaars A., et al. (1999) Mutational spectrum of the TSC1 gene in cohort of 225 tuberous sclerosis complex patients: no evidence for genotype-phenotype correlation. J. Med. Genet. 36, 285–289.

    PubMed  Google Scholar 

  • Weiner H. L. (2004) Tuberous sclerosis and multiple tubers: localizing the epileptogenic zone. Epilepsia 45 (Suppl. 4), 41–42.

    PubMed  Google Scholar 

  • Wenzel H. J., Patel L. S., Robbins C. A., Emmi A., Yeung R. S., and Schwartzkroin P. A. (2004) Morphology of Cerebral Lesions in the Eker Rat Model of Tuberous Sclerosis. Acta Neuropathol. 108, 97–108.

    PubMed  Google Scholar 

  • White R., Hua Y., Scheithauer B., Lynch D. R., Henske E. P., and Crino P. B. (2001) Selective Alterations in Glutamate and GABAReceptor Subunit mRNA Expression in Dysplastic Neurons and Giant Cells of Cortical Tubers. Ann. Neurol. 49, 67–78.

    PubMed  CAS  Google Scholar 

  • Wienecke R., Maize J. C. Jr., Shoarinejad F., et al. (1996) Co-localization of the TSC2 product tuberin with its target Rap1 in the Golgi apparatus. Oncogene 13, 913–923.

    PubMed  CAS  Google Scholar 

  • Wong M., Ess K. C., Uhlmann E. J., et al. (2003) Impaired glial glutamate transport in a mouse tuberous sclerosis epilepsy model. Ann. Neurol. 54, 251–256.

    PubMed  CAS  Google Scholar 

  • Xiao G. H., Shoarinejad F., Jin F., Golemis E. A., and Yeung R. S. (1997) The tuberous sclerosis 2 gene product, tuberin, functions as a Rab5 GTPase activating protein (GAP) in modulating endocytosis. J. Biol. Chem. 272, 6097–6100.

    PubMed  CAS  Google Scholar 

  • Yamanouchi H., Jay V., Rutka J. T., Takashima S., and Becker L. E. (1997) Evidence of abnormal differentiation in giant cells of tuberous sclerosis. Pediatr. Neurol. 17, 49–53.

    PubMed  CAS  Google Scholar 

  • Yeung R. S., Katsetos C. D., and Klein-Szanto A. (1997) Subependymal astrocytic hamartomas in the Eker rat model of tuberous sclerosis. Am. J. Pathol. 151, 1477–1486.

    PubMed  CAS  Google Scholar 

  • Zhang Y., Gao X., Saucedo L. J., Ru B., Edgar B. A., and Pan D. (2003) Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat. Cell Biol. 5, 578–581.

    PubMed  CAS  Google Scholar 

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    Leah Marcotte & Peter B. Crino

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Marcotte, L., Crino, P.B. The neurobiology of the tuberous sclerosis complex. Neuromol Med 8, 531–546 (2006). https://doi.org/10.1385/NMM:8:4:531

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  • DOI: https://doi.org/10.1385/NMM:8:4:531

Keywords

  • Tuberous Sclerosis
  • Tuberous Sclerosis Complex
  • Tuberin
  • Infantile Spasm
  • NeuroMolecular Medicine Volume