1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Genomics and Human Genetics
  4. Volume 20, 2019
  5. Article

Annual Review of Genomics and Human Genetics

Volume 20, 2019

Genetic Etiologies, Diagnosis, and Treatment of Tuberous Sclerosis Complex

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that affects multiple organ systems due to an inactivating variant in either or , resulting in the hyperactivation of the mechanistic target of rapamycin (mTOR) pathway. Dysregulated mTOR signaling results in increased cell growth and proliferation. Clinically, TSC patients exhibit great phenotypic variability, but the neurologic and neuropsychiatric manifestations of the disease have the greatest morbidity and mortality. TSC-associated epilepsy occurs in nearly all patients and is often difficult to treat because it is refractory to multiple antiseizure medications. The advent of mTOR inhibitors offers great promise in the treatment of TSC-associated epilepsy and other neurodevelopmental manifestations of the disease; however, the optimal timing of therapeutic intervention is not yet fully understood.

Keyword(s): epilepsy, genetics, mTOR, rapamycin, tuberous sclerosis
Loading

Article metrics loading...

/content/journals/10.1146/annurev-genom-083118-015354
2019-08-31
2025-02-10
Loading full text...

Full text loading...

/deliver/fulltext/genom/20/1/annurev-genom-083118-015354.html?itemId=/content/journals/10.1146/annurev-genom-083118-015354&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Agrawal P, Reynolds J, Chew S, Lamba DA, Hughes RE 2014. DEPTOR is a stemness factor that regulates pluripotency of embryonic stem cells. J. Biol. Chem. 289:31818–26
     [Google Scholar]
  2. 2.
    Ali M, Girimaji SC, Kumar A 2003. Identification of a core promoter and a novel isoform of the human TSC1 gene transcript and structural comparison with mouse homolog. Gene 320:145–54
     [Google Scholar]
  3. 3.
    Avgeris S, Fostira F, Vagena A, Ninios Y, Delimitsou A et al. 2017. Mutational analysis of TSC1 and TSC2 genes in tuberous sclerosis complex patients from Greece. Sci. Rep. 7:16697
     [Google Scholar]
  4. 4.
    Barnes AP, Polleux F. 2009. Establishment of axon-dendrite polarity in developing neurons. Annu. Rev. Neurosci. 32:347–81
     [Google Scholar]
  5. 5.
    Bateup HS, Takasaki KT, Saulnier JL, Denefrio CL, Sabatini BL 2011. Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function. J. Neurosci. 31:8862–69
     [Google Scholar]
  6. 6.
    Bercury KK, Dai J, Sachs HH, Ahrendsen JT, Wood TL, Macklin WB 2014. Conditional ablation of Raptor or Rictor has differential impact on oligodendrocyte differentiation and CNS myelination. J. Neurosci. 34:4466–80
     [Google Scholar]
  7. 7.
    Bessis D, Malinge MC, Girard C 2018. Isolated and unilateral facial angiofibromas revealing a type 1 segmental postzygotic mosaicism of tuberous sclerosis complex with c.4949_4982del TSC2 mutation. Br. J. Dermatol. 178:e53–54
     [Google Scholar]
  8. 8.
    Caban C, Khan N, Hasbani DM, Crino PB 2016. Genetics of tuberous sclerosis complex: implications for clinical practice. Appl. Clin. Genet. 10:1–8
     [Google Scholar]
  9. 9.
    Canevini MP, Kotulska-Jozwiak K, Curatolo P, La Briola F, Peron A et al. 2018. Current concepts on epilepsy management in tuberous sclerosis complex. Am. J. Med. Genet. C 178:299–308
     [Google Scholar]
  10. 10.
    Capal JK, Bernardino-Cuesta B, Horn PS, Murray D, Byars AW et al. 2017. Influence of seizures on early development in tuberous sclerosis complex. Epilepsy Behav 70:245–52
     [Google Scholar]
  11. 11.
    Carbonara C, Longa L, Grosso E, Borrone C, Garré MG et al. 1994. 9q34 loss of heterozygosity in a tuberous sclerosis astrocytoma suggests a growth suppressor-like activity also for the TSC1 gene. Hum. Mol. Genet. 3:1829–32
     [Google Scholar]
  12. 12.
    Carsillo T, Astrinidis A, Henske EP 2000. Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. PNAS 97:6085–90
     [Google Scholar]
  13. 13.
    Chan JA, Zhang H, Roberts PS, Jozwiak S, Wieslawa G 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. 63:1236–42
     [Google Scholar]
  14. 14.
    Choi Y-J, Di Nardo A, Kramvis I, Meikle L, Kwiatkowski DJ et al. 2008. Tuberous sclerosis complex proteins control axon formation. Genes Dev 22:2485–95
     [Google Scholar]
  15. 15.
    Chow DK, Groszer M, Pribadi M, Machniki M, Carmichael ST et al. 2009. Laminar and compartmental regulation of dendritic growth in mature cortex. Nat. Neurosci. 12:116–18
     [Google Scholar]
  16. 16.
    Chu-Shore CJ, Major P, Camposano S, Muzykewicz D, Thiele EA 2010. The natural history of epilepsy in tuberous sclerosis complex. Epilepsia 51:1236–41
     [Google Scholar]
  17. 17.
    Cloetta D, Thomanetz V, Baranek C, Lustenberger RM, Lin S et al. 2013. Inactivation of mTORC1 in the developing brain causes microcephaly and affects gliogenesis. J. Neurosci. 33:7799–810
     [Google Scholar]
  18. 18.
    Coevoets R, Arican S, Hoogeveen-Westerveld M, Simons E, van den Ouweland A et al. 2009. A reliable cell-based assay for testing unclassified TSC2 gene variants. Eur. J. Hum. Genet. 17:301–10
     [Google Scholar]
  19. 19.
    Costa V, Aigner S, Vukcevic M, Sauter E, Behr K et al. 2016. mTORC1 inhibition corrects neurodevelopmental and synaptic alterations in a human stem cell model of tuberous sclerosis. Cell Rep 15:86–95
     [Google Scholar]
  20. 20.
    Crino PB, Nathanson KL, Henske EP 2006. The tuberous sclerosis complex. N. Engl. J. Med. 355:1345–56
     [Google Scholar]
  21. 21.
    Curatolo P. 2015. Mechanistic target of rapamycin (mTOR) in tuberous sclerosis complex-associated epilepsy. Pediatr. Neurol. 52:281–89
     [Google Scholar]
  22. 22.
    Curatolo P, Bombardieri R, Jozwiak S 2008. Tuberous sclerosis. Lancet 372:657–68
     [Google Scholar]
  23. 23.
    Curatolo P, Franz DN, Lawson JA, Yapici Z, Ikeda H et al. 2018. Adjunctive everolimus for children and adolescents with treatment-refractory seizures associated with tuberous sclerosis complex: post-hoc analysis of the phase 3 EXIST-3 trial. Lancet Child Adolesc. Heal. 2:495–504
     [Google Scholar]
  24. 24.
    Curatolo P, Moavero R, Roberto D, Graziola F 2015. Genotype/phenotype correlations in tuberous sclerosis complex. Semin. Pediatr. Neurol. 22:259–73
     [Google Scholar]
  25. 25.
    Dabora SL, Jozwiak S, Franz DN, Roberts PS, Nieto A 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
     [Google Scholar]
  26. 26.
    de Vries PJ, Belousova E, Benedik MP, Carter T, Cottin V et al. 2018. TSC-associated neuropsychiatric disorders (TAND): findings from the TOSCA natural history study. Orphanet J. Rare Dis. 13:157
     [Google Scholar]
  27. 27.
    de Vries PJ, Whittemore VH, Leclezio L, Byars AW, Dunn D et al. 2015. Tuberous sclerosis associated neuropsychiatric disorders (TAND) and the TAND checklist. Pediatr. Neurol. 52:25–35
     [Google Scholar]
  28. 28.
    Dibble CC, Elis W, Menon S, Qin W, Klekota J et al. 2012. TBC1D7 is a third subunit of the TSC1-TSC2 complex upstream of mTORC1. Mol. Cell 47:535–46
     [Google Scholar]
  29. 29.
    DiMario FJ, Sahin M, Ebrahimi-Fakhari D 2015. Tuberous sclerosis complex. Pediatr. Clin. N. Am. 62:633–48
     [Google Scholar]
  30. 30.
    Dowling RJO, Topisirovic I, Alain T, Bidinosti M, Fonseca BD et al. 2010. mTORCI-mediated cell proliferation, but not cell growth, controlled by the 4E-BPs. Science 328:1172–76
     [Google Scholar]
  31. 31.
    Easton RM, Cho H, Roovers K, Shineman DW, Mizrahi M et al. 2005. Role for Akt3/Protein kinase B in attainment of normal brain size. Mol. Cell. Biol. 25:1869–78
     [Google Scholar]
  32. 32.
    Ehninger D, Han S, Shilyansky C, Zhou Y, Li W et al. 2008. Reversal of learning deficits in a Tsc2+/− mouse model of tuberous sclerosis. Nat. Med. 14:843–48
     [Google Scholar]
  33. 33.
    Ekim B, Magnuson B, Acosta-Jaquez HA, Keller JA, Feener EP, Fingar DC 2011. mTOR kinase domain phosphorylation promotes mTORC1 signaling, cell growth, and cell cycle progression. Mol. Cell. Biol. 31:2787–801
     [Google Scholar]
  34. 34.
    Ekong R, Nellist M, Hoogeveen-Westerveld M, Wentink M, Panzer J et al. 2016. Variants within TSC2 exons 25 and 31 are very unlikely to cause clinically diagnosable tuberous sclerosis. Hum. Mutat. 37:364–70
     [Google Scholar]
  35. 35.
    Ercan E, Han JM, Di Nardo A, Winden K, Han M-J et al. 2017. Neuronal CTGF/CCN2 negatively regulates myelination in a mouse model of tuberous sclerosis complex. J. Exp. Med. 214:681–97
     [Google Scholar]
  36. 36.
    Eur. Chromosome 16 Tuberous Scler. Consort 1993. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 75:1305–15
     [Google Scholar]
  37. 37.
    Feliciano DM, Lin TV, Hartman NW, Bartley CM, Kubera C et al. 2013. A circuitry and biochemical basis for tuberous sclerosis symptoms: from epilepsy to neurocognitive deficits. Int. J. Dev. Neurosci. 31:667–78
     [Google Scholar]
  38. 38.
    Feliciano DM, Quon JL, Su T, Taylor MM, Bordey A 2012. Postnatal neurogenesis generates heterotopias, olfactory micronodules and cortical infiltration following single-cell TSC1 deletion. Hum. Mol. Genet. 21:799–810
     [Google Scholar]
  39. 39.
    Feliciano DM, Su T, Lopez J, Platel JC, Bordey A 2011. Single-cell Tsc1 knockout during corticogenesis generates tuber-like lesions and reduces seizure threshold in mice. J. Clin. Investig. 121:1596–607
     [Google Scholar]
  40. 40.
    Fokkema IFAC, Taschner PEM, Schaafsma GCP, Celli J, Laros JFJ, den Dunnen JT 2011. LOVD v.2.0: the next generation in gene variant databases. Hum. Mutat. 32:557–63
     [Google Scholar]
  41. 41.
    Franz DN, Belousova E, Sparagana S, Bebin EM, Frost MD et al. 2016. Long-term use of everolimus in patients with tuberous sclerosis complex: final results from the EXIST-1 study. PLOS ONE 11:e0158476
     [Google Scholar]
  42. 42.
    Franz DN, Bissler JJ, McCormack FX 2010. Tuberous sclerosis complex: neurological, renal and pulmonary manifestations. Neuropediatrics 41:199–208
     [Google Scholar]
  43. 43.
    Fryer AE, Chalmers A, Connor JM, Fraser I, Povey S et al. 1987. Evidence that the gene for tuberous sclerosis is on chromosome 9. Lancet 329:659–61
     [Google Scholar]
  44. 44.
    Fu C, Cawthon B, Clinkscales W, Bruce A, Winzenburger P, Ess KC 2012. GABAergic interneuron development and function is modulated by the Tsc1 gene. Cereb. Cortex 22:2111–19
     [Google Scholar]
  45. 45.
    Gai Z, Chu W, Deng W, Li W, Li H et al. 2016. Structure of the TBC1D7-TSC1 complex reveals that TBC1D7 stabilizes dimerization of the TSC1 C-terminal coiled coil region. J. Mol. Cell Biol. 8:411–25
     [Google Scholar]
  46. 46.
    Gangloff Y-G, Mueller M, Dann SG, Svoboda P, Sticker M et al. 2004. Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development. Mol. Cell. Biol. 24:9508–16
     [Google Scholar]
  47. 47.
    Giannikou K, Malinowska IA, Pugh TJ, Yan R, Tseng YY et al. 2016. Whole exome sequencing identifies TSC1/TSC2 biallelic loss as the primary and sufficient driver event for renal angiomyolipoma development. PLOS Genet 12:e1006242
     [Google Scholar]
  48. 48.
    Gong X, Zhang L, Huang T, Lin TV, Miyares L et al. 2015. Activating the translational repressor 4E-BP or reducing S6K-GSK3β activity prevents accelerated axon growth induced by hyperactive mTOR in vivo. Hum. Mol. Genet. 24:5746–58
     [Google Scholar]
  49. 49.
    Goorden SMI, van Woerden GM, van der Weerd L, Cheadle JP, Elgersma Y 2007. Cognitive deficits in Tsc1+/− mice in the absence of cerebral lesions and seizures. Ann. Neurol. 62:648–55
     [Google Scholar]
  50. 50.
    Goto J, Talos DM, Klein P, Qin W, Chekaluk YI et al. 2011. Regulable neural progenitor-specific Tsc1 loss yields giant cells with organellar dysfunction in a model of tuberous sclerosis complex. PNAS 108:E1070–79
     [Google Scholar]
  51. 51.
    Grabole N, Zhang JD, Aigner S, Ruderisch N, Costa V et al. 2016. Genomic analysis of the molecular neuropathology of tuberous sclerosis using a human stem cell model. Genome Med 8:94
     [Google Scholar]
  52. 52.
    Green AJ, Johnson PH, Yates JRW 1994. The tuberous sclerosis gene on chromosome 9q34 acts as a growth suppressor. Hum. Mol. Genet. 3:1833–34
     [Google Scholar]
  53. 53.
    Green AJ, Smith M, Yates JR 1994. Loss of heterozygosity on chromosome 16p13.3 in hamartomas from tuberous sclerosis patients. Nat Genet 6:193–96
     [Google Scholar]
  54. 54.
    Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY et al. 2006. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCα, but not S6K1. Dev. Cell. 11:859–71
     [Google Scholar]
  55. 55.
    Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A et al. 2008. AMPK phosphorylation of Raptor mediates a metabolic checkpoint. Mol. Cell. 30:214–26
     [Google Scholar]
  56. 56.
    Hancock E, Osborne JP. 1999. Vigabatrin in the treatment of infantile spasms in tuberous sclerosis: literature review. J. Child Neurol. 14:71–74
     [Google Scholar]
  57. 57.
    Hartman NW, Lin TV, Zhang L, Paquelet GE, Feliciano DM, Bordey A 2013. mTORC1 targets the translational repressor 4E-BP2, but not S6 kinase 1/2, to regulate neural stem cell self-renewal in vivo. Cell Rep 5:433–44
     [Google Scholar]
  58. 58.
    Henry FE, Hockeimer W, Chen A, Mysore SP, Sutton MA 2017. Mechanistic target of rapamycin is necessary for changes in dendritic spine morphology associated with long-term potentiation. Mol. Brain. 10:50
     [Google Scholar]
  59. 59.
    Henske EP, Jóźwiak S, Kingswood JC, Sampson JR, Thiele EA 2016. Tuberous sclerosis complex. Nat. Rev. Dis. Prim. 2:16035
     [Google Scholar]
  60. 60.
    Hoogeveen-Westerveld M, Ekong R, Povey S, Karbassi I, Batish S et al. 2012. Functional assessment of TSC1 missense variants identified in individuals with tuberous sclerosis complex. Hum. Mutat. 33:476–79
     [Google Scholar]
  61. 61.
    Hoogeveen-Westerveld M, Ekong R, Povey S, Mayer K, Lannoy N et al. 2013. Functional assessment of TSC2 variants identified in individuals with tuberous sclerosis complex. Hum. Mutat. 34:167–75
     [Google Scholar]
  62. 62.
    Hoogeveen-Westerveld M, Exalto C, Maat-Kievit A, van den Ouweland A, Halley D, Nellist M 2010. Analysis of TSC1 truncations defines regions involved in TSC1 stability, aggregation and interaction. Biochim. Biophys. Acta 1802:774–81
     [Google Scholar]
  63. 63.
    Hoogeveen-Westerveld M, Wentink M, van den Heuvel D, Mozaffari M, Ekong R et al. 2011. Functional assessment of variants in the TSC1 and TSC2 genes identified in individuals with tuberous sclerosis complex. Hum. Mutat. 32:424–35
     [Google Scholar]
  64. 64.
    Huang J, Dibble CC, Matsuzaki M, Manning BD 2008. The TSC1-TSC2 complex is required for proper activation of mTOR complex 2. Mol. Cell. Biol. 28:4104–15
     [Google Scholar]
  65. 65.
    Jacinto E, Facchinetti V, Liu D, Soto N, Wei S et al. 2006. SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127:125–37
     [Google Scholar]
  66. 66.
    Jacinto E, Loewith R, Schmidt A, Lin S, Rüegg MA et al. 2004. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell Biol. 6:1122–28
     [Google Scholar]
  67. 67.
    Jaworski J, Spangler S, Seeburg DP, Hoogenraad CC, Sheng M 2005. Control of dendritic arborization by the phosphoinositide-3′-kinase-Akt-mammalian target of rapamycin pathway. J. Neurosci. 25:11300–12
     [Google Scholar]
  68. 68.
    Jo H, Schieve LA, Rice CE, Yeargin-Allsopp M, Tian LH et al. 2015. Age at autism spectrum disorder (ASD) diagnosis by race, ethnicity, and primary household language among children with special health care needs, United States, 2009–2010. Matern. Child Health J. 19:1687–97
     [Google Scholar]
  69. 69.
    Jones AC, Shyamsundar MM, Thomas MW, Maynard J, Idziaszczyk S et al. 1999. Comprehensive mutation analysis of TSC1 and TSC2—and phenotypic correlations in 150 families with tuberous sclerosis. Am. J. Hum. Genet. 64:1305–15
     [Google Scholar]
  70. 70.
    Ka M, Condorelli G, Woodgett JR, Kim W-Y 2014. mTOR regulates brain morphogenesis by mediating GSK3 signaling. Development 14:4076–86
     [Google Scholar]
  71. 71.
    Knudson A. 1971. Mutation and cancer: statistical study of retinoblastoma. PNAS 68:820–23
     [Google Scholar]
  72. 72.
    Kobayashi T, Minowa O, Kuno J, Mitani H, Hino O, Noda T 1999. Renal carcinogenesis, hepatic hemangiomatosis, and embryonic lethality caused by a germ-line Tsc2 mutation in mice. Cancer Res 59:1206–11
     [Google Scholar]
  73. 73.
    Kobayashi T, Minowa O, Sugitani Y, Takai S, Mitani H et al. 2001. A germ-line Tsc1 mutation causes tumor development and embryonic lethality that are similar, but not identical to, those caused by Tsc2 mutation in mice. PNAS 98:8762–67
     [Google Scholar]
  74. 74.
    Kozlowski P, Roberts P, Dabora S, Franz D, Bissler J et al. 2007. Identification of 54 large deletions/duplications in TSC1 and TSC2 using MLPA, and genotype-phenotype correlations. Hum. Genet. 121:389–400
     [Google Scholar]
  75. 75.
    Kumar V. 2005. Regulation of dendritic morphogenesis by Ras-PI3K-Akt-mTOR and Ras-MAPK signaling pathways. J. Neurosci. 25:11288–99
     [Google Scholar]
  76. 76.
    Kwiatkowski DJ. 2002. A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells. Hum. Mol. Genet. 11:525–34
     [Google Scholar]
  77. 77.
    Laplante M, Sabatini DM. 2009. mTOR signaling at a glance. J. Cell Sci. 122:3589–94
     [Google Scholar]
  78. 78.
    Laplante M, Sabatini DM, Aggarwal D, Fernandez ML, Soliman GA et al. 2012. mTOR signaling in growth control and disease. Cell 149:274–93
     [Google Scholar]
  79. 79.
    Lebrun-Julien F, Bachmann L, Norrmen C, Trotzmuller M, Kofeler H et al. 2014. Balanced mTORC1 activity in oligodendrocytes is required for accurate CNS myelination. J. Neurosci. 34:8432–48
     [Google Scholar]
  80. 80.
    Li YH, Werner H, Püschel AW 2008. Rheb and mTOR regulate neuronal polarity through Rap1B. J. Biol. Chem. 283:33784–92
     [Google Scholar]
  81. 81.
    LiCausi F, Hartman NW. 2018. Role of mTOR complexes in neurogenesis. Int. J. Mol. Sci. 19:1544
     [Google Scholar]
  82. 82.
    Lim JS, Gopalappa R, Kim SH, Ramakrishna S, Lee M et al. 2017. Somatic mutations in TSC1 and TSC2 cause focal cortical dysplasia. Am. J. Hum. Genet. 100:454–72
     [Google Scholar]
  83. 83.
    Lin TV, Hsieh L, Kimura T, Malone TJ, Bordey A 2016. Normalizing translation through 4E-BP prevents mTOR-driven cortical mislamination and ameliorates aberrant neuron integration. PNAS 113:11330–35
     [Google Scholar]
  84. 84.
    Liu P, Begley M, Michowski W, Inuzuka H, Ginzberg M et al. 2014. Cell-cycle-regulated activation of Akt kinase by phosphorylation at its carboxyl terminus. Nature 508:541–45
     [Google Scholar]
  85. 85.
    Liu P, Gan W, Chin YR, Ogura K, Guo J et al. 2015. Ptdins(3,4,5)P3-dependent activation of the mTORC2 kinase complex. Cancer Discov 5:1194–209
     [Google Scholar]
  86. 86.
    Lozovaya N, Gataullina S, Tsintsadze T, Tsintsadze V, Pallesi-Pocachard E et al. 2014. Selective suppression of excessive GluN2C expression rescues early epilepsy in a tuberous sclerosis murine model. Nat. Commun. 5:4563
     [Google Scholar]
  87. 87.
    Magri L, Cambiaghi M, Cominelli M, Alfaro-Cervello C, Cursi M et al. 2011. Sustained activation of mTOR pathway in embryonic neural stem cells leads to development of tuberous sclerosis complex-associated lesions. Cell Stem Cell 9:447–62
     [Google Scholar]
  88. 88.
    Magri L, Cominelli M, Cambiaghi M, Cursi M, Leocani L et al. 2013. Timing of mTOR activation affects tuberous sclerosis complex neuropathology in mouse models. Dis. Model. Mech. 6:1185–97
     [Google Scholar]
  89. 89.
    Mandell DS, Novak MM, Zubritsky CD 2005. Factors associated with age of diagnosis among children with autism spectrum disorders. Pediatrics 116:1480–86
     [Google Scholar]
  90. 90.
    Martin KR, Zhou W, Bowman MJ, Shih J, Au KS et al. 2017. The genomic landscape of tuberous sclerosis complex. Nat. Commun. 8:15816
     [Google Scholar]
  91. 91.
    Meikle L, Pollizzi K, Egnor A, Kramvis I, Lane H et al. 2008. Response of a neuronal model of tuberous sclerosis to mammalian target of rapamycin (mTOR) inhibitors: Effects on mTORC1 and Akt signaling lead to improved survival and function. J. Neurosci. 28:5422–32
     [Google Scholar]
  92. 92.
    Meikle L, Talos DM, Onda H, Pollizzi K, Rotenberg A et al. 2007. A mouse model of tuberous sclerosis: Neuronal loss of Tsc1 causes dysplastic and ectopic neurons, reduced myelination, seizure activity, and limited survival. J. Neurosci. 27:5546–58
     [Google Scholar]
  93. 93.
    Morita T, Sobuě K. 2009. Specification of neuronal polarity regulated by local translation of CRMP2 and Tau via the mTOR-p70S6K pathway. J. Biol. Chem. 284:27734–45
     [Google Scholar]
  94. 94.
    Nellist M, van den Heuvel D, Schluep D, Exalto C, Goedbloed M et al. 2009. Missense mutations to the TSC1 gene cause tuberous sclerosis complex. Eur. J. Hum. Genet. 17:319–28
     [Google Scholar]
  95. 95.
    Nellist M, van Slegtenhorst MA, Goedbloed M, van den Ouweland A, Halley DJJ, van der Sluijs P 1999. Characterization of the cytosolic tuberin-hamartin complex. Tuberin is a cytosolic chaperone for hamartin. J. Biol. Chem. 274:35647–52
     [Google Scholar]
  96. 96.
    Nie D, Di Nardo A, Han JM, Baharanyi H, Kramvis I et al. 2010. Tsc2-Rheb signaling regulates EphA-mediated axon guidance. Nat. Neurosci. 13:163–72
     [Google Scholar]
  97. 97.
    Northrup H, Krueger DA (Int. Tuberous Scler. Complex Consens. Group) 2013. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr. Neurol 49:243–54
     [Google Scholar]
  98. 98.
    Nowakowski TJ, Bhaduri A, Pollen AA, Alvarado B, Mostajo-Radji MA et al. 2017. Spatiotemporal gene expression trajectories reveal developmental hierarchies of the human cortex. Science 358:1318–23
     [Google Scholar]
  99. 99.
    O'Callaghan FJ, Shiell AW, Osborne JP, Martyn CN 1998. Prevalence of tuberous sclerosis estimated by capture-recapture analysis. Lancet 351:1490
     [Google Scholar]
  100. 100.
    Orlova KA, Crino PB. 2010. The tuberous sclerosis complex. Ann. N.Y. Acad. Sci. 1184:87–105
     [Google Scholar]
  101. 101.
    Paliouras GN, Hamilton LK, Aumont A, Joppe SE, Barnabe-Heider F, Fernandes KJL 2012. Mammalian target of rapamycin signaling is a key regulator of the transit-amplifying progenitor pool in the adult and aging forebrain. J. Neurosci. 32:15012–26
     [Google Scholar]
  102. 102.
    Park SH, Pepkowitz SH, Kerfoot C, De Rosa MJ, Poukens V et al. 1997. Tuberous sclerosis in a 20-week gestation fetus: immunohistochemical study. Acta Neuropathol 94:180–86
     [Google Scholar]
  103. 103.
    Peron A, Au KS, Northrup H 2018. Genetics, genomics, and genotype-phenotype correlations of TSC: insights for clinical practice. Am. J. Med. Genet. 178:281–90
     [Google Scholar]
  104. 104.
    Pitkänen A, Lukasiuk K, Dudek FE, Staley KJ 2015. Epileptogenesis. Cold Spring Harb. Perspect. Med. 5:a022822
     [Google Scholar]
  105. 105.
    Pollen AA, Nowakowski TJ, Chen J, Retallack H, Sandoval-Espinosa C et al. 2015. Molecular identity of human outer radial glia during cortical development. Cell 163:55–67
     [Google Scholar]
  106. 106.
    Povey S, Ekong R. 2018. Tuberous sclerosis database: tuberous sclerosis 1 (TSC1) Leiden Open Var. Database, version 2 (LOVD2), accessed Nov. 15, 2018. http://www.lovd.nl/TSC1
    [Google Scholar]
  107. 107.
    Povey S, Ekong R. 2018. Tuberous sclerosis database: tuberous sclerosis 2 (TSC2) Leiden Open Var. Database, version 2 (LOVD2), accessed May 7, 2018. http://www.lovd.nl/TSC2
    [Google Scholar]
  108. 108.
    Prabowo AS, Anink JJ, Lammens M, Nellist M, van den Ouweland A et al. 2013. Fetal brain lesions in tuberous sclerosis complex: TORC1 activation and inflammation. Brain Pathol 23:45–59
     [Google Scholar]
  109. 109.
    Raju GP, Urion DK, Sahin M 2007. Neonatal subependymal giant cell astrocytoma: new case and review of literature. Pediatr. Neurol. 36:128–31
     [Google Scholar]
  110. 110.
    Ruppe V, Dilsiz P, Reiss CS, Carlson C, Devinsky O et al. 2014. Developmental brain abnormalities in tuberous sclerosis complex: a comparative tissue analysis of cortical tubers and perituberal cortex. Epilepsia 55:539–50
     [Google Scholar]
  111. 111.
    Sampson JR, Maheshwar MM, Aspinwall R, Thompson P, Cheadle JP et al. 1997. Renal cystic disease in tuberous sclerosis: role of the polycystic kidney disease 1 gene. Am. J. Hum. Genet. 61:843–51
     [Google Scholar]
  112. 112.
    Sancak O, Nellist M, Goedbloed M, Elfferich P, Wouters C 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. 13:731–41
     [Google Scholar]
  113. 113.
    Santiago Lima AJ, Hoogeveen-Westerveld M, Nakashima A, Maat-Kievit A, van den Ouweland A et al. 2014. Identification of regions critical for the integrity of the TSC1-TSC2-TBC1D7 complex. PLOS ONE 9:e93940
     [Google Scholar]
  114. 114.
    Sarbassov DD, Guertin DA, Ali SM, Sabatini DM 2005. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–101
     [Google Scholar]
  115. 115.
    Saxton RA, Sabatini DM. 2017. mTOR Signaling in growth, metabolism, and disease. Cell 168:960–76
     [Google Scholar]
  116. 116.
    Stiles J, Jernigan TL. 2010. The basics of brain development. Neuropsychol. Rev. 20:327–48
     [Google Scholar]
  117. 117.
    Sugiura H, Yasuda S, Katsurabayashi S, Kawano H, Endo K et al. 2015. Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex. Nat. Commun. 6:6842
     [Google Scholar]
  118. 118.
    Sun W, Zhu YJ, Wang Z, Zhong Q, Gao F et al. 2013. Crystal structure of the yeast TSC1 core domain and implications for tuberous sclerosis pathological mutations. Nat. Commun. 4:2135
     [Google Scholar]
  119. 119.
    Takei N, Nawa H. 2014. mTOR signaling and its roles in normal and abnormal brain development. Front. Mol. Neurosci. 7:28
     [Google Scholar]
  120. 120.
    Talos DM, Kwiatkowski DJ, Cordero K, Black PM, Jensen FE 2008. Cell-specific alterations of glutamate receptor expression in tuberous sclerosis complex cortical tubers. Ann. Neurol. 63:454–65
     [Google Scholar]
  121. 121.
    Talos DM, Sun H, Kosaras B, Joseph A, Folkerth RD et al. 2012. Altered inhibition in tuberous sclerosis and type IIb cortical dysplasia. Ann. Neurol. 71:539–51
     [Google Scholar]
  122. 122.
    Tang SJ, Reis G, Kang H, Gingras A-C, Sonenberg N, Schuman EM 2002. A rapamycin-sensitive signaling pathway contributes to long-term synaptic plasticity in the hippocampus. PNAS 99:467–72
     [Google Scholar]
  123. 123.
    Tavazoie SF, Alvarez VA, Ridenour DA, Kwiatkowski DJ, Sabatini BL 2005. Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat. Neurosci. 8:1727–34
     [Google Scholar]
  124. 124.
    Tee AR, Sampson JR, Pal DK, Bateman JM 2016. The role of mTOR signalling in neurogenesis, insights from tuberous sclerosis complex. Semin. Cell Dev. Biol. 52:12–20
     [Google Scholar]
  125. 125.
    Thomanetz V, Angliker N, Cloëtta D, Lustenberger RM, Schweighauser M et al. 2013. Ablation of the mTORC2 component rictor in brain or Purkinje cells affects size and neuron morphology. J. Cell Biol. 201:293–308
     [Google Scholar]
  126. 126.
    Traynelis SF, Wollmuth LP, McBain CJ, Menniti FS, Vance KM et al. 2010. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol. Rev. 62:405–96
     [Google Scholar]
  127. 127.
    Tsai PT, Hull C, Chu Y, Greene-Colozzi E, Sadowski AR et al. 2012. Autistic-like behaviour and cerebellar dysfunction in Purkinje cell Tsc1 mutant mice. Nature 488:647–51
     [Google Scholar]
  128. 128.
    Tsai PT, Rudolph S, Guo C, Ellegood J, Gibson JM et al. 2018. Sensitive periods for cerebellar-mediated autistic-like behaviors. Cell Rep 25:357–67
     [Google Scholar]
  129. 129.
    Tsai V, Parker WE, Orlova KA, Baybis M, Chi AWS et al. 2014. Fetal brain mTOR signaling activation in tuberous sclerosis complex. Cereb. Cortex 24:315–27
     [Google Scholar]
  130. 130.
    Tsokas P. 2005. Local protein synthesis mediates a rapid increase in dendritic elongation factor 1A after induction of late long-term potentiation. J. Neurosci. 25:5833–43
     [Google Scholar]
  131. 131.
    Tyburczy ME, Dies KA, Glass J, Camposano S, Chekaluk Y et al. 2015. Mosaic and intronic mutations in TSC1/TSC2 explain the majority of TSC patients with no mutation identified by conventional testing. PLOS Genet 11:e1005637
     [Google Scholar]
  132. 132.
    Tyburczy ME, Wang JA, Li S, Thangapazham R, Chekaluk Y et al. 2014. Sun exposure causes somatic second-hit mutations and angiofibroma development in tuberous sclerosis complex. Hum. Mol. Genet. 23:2023–29
     [Google Scholar]
  133. 133.
    Tyler WA, Jain MR, Cifelli SE, Li Q, Ku L et al. 2011. Proteomic identification of novel targets regulated by the mammalian target of rapamycin pathway during oligodendrocyte differentiation. Glia 59:1754–69
     [Google Scholar]
  134. 134.
    UniProt Consort 2017. UniProt: the universal protein knowledgebase. Nucleic Acids Res 45:D158–69
     [Google Scholar]
  135. 135.
    Urbanska M, Gozdz A, Swiech LJ, Jaworski J 2012. Mammalian target of rapamycin complex 1 (mTORC1) and 2 (mTORC2) control the dendritic arbor morphology of hippocampal neurons. J. Biol. Chem. 287:30240–56
     [Google Scholar]
  136. 136.
    van Eeghen AM, Nellist M, van Eeghen EE, Thiele EA 2013. Central TSC2 missense mutations are associated with a reduced risk of infantile spasms. Epilepsy Res 103:83–87
     [Google Scholar]
  137. 137.
    van Slegtenhorst M, De Hoogt R, Hermans C, Nellist M, Janssen B et al. 1997. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 277:805–8
     [Google Scholar]
  138. 138.
    van Slegttenhorst M, Nellist M, Nagelkerken B, Cheadle J, Snell R et al. 1998. Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum. Mol. Genet. 7:1053–58
     [Google Scholar]
  139. 139.
    Verhoef S, Bakker L, Tempelaars AMP, Hesseling-Janssen ALW, Mazurczak T et al. 1999. High rate of mosaicism in tuberous sclerosis complex. Am. J. Hum. Genet. 64:1632–37
     [Google Scholar]
  140. 140.
    Wahane SD, Hellbach N, Prentzell MT, Weise SC, Vezzali R et al. 2014. PI3K-p110-alpha-subtype signalling mediates survival, proliferation and neurogenesis of cortical progenitor cells via activation of mTORC2. J. Neurochem. 130:255–67
     [Google Scholar]
  141. 141.
    Way SW, McKenna J III, Mietzsch U, Reith RM, Wu HCJ, Gambello MJ 2009. Loss of Tsc2 in radial glia models the brain pathology of tuberous sclerosis complex in the mouse. Hum. Mol. Genet. 18:1252–65
     [Google Scholar]
  142. 142.
    Winden KD, Ebrahimi-Fakhari D, Sahin M 2018. Abnormal mTOR activation in autism. Annu. Rev. Neurosci. 41:1–23
     [Google Scholar]
  143. 143.
    Wong ROL, Ghosh A. 2002. Activity-dependent regulation of dendritic growth and patterning. Nat. Rev. Neurosci. 3:803–12
     [Google Scholar]
  144. 144.
    Yang H, Rudge DG, Koos JD, Vaidialingam B, Yang HJ, Pavletich NP 2013. mTOR kinase structure, mechanism and regulation. Nature 497:217–23
     [Google Scholar]
  145. 145.
    Yoshihara Y, De Roo M, Muller D 2009. Dendritic spine formation and stabilization. Curr. Opin. Neurobiol. 19:146–53
     [Google Scholar]
  146. 146.
    Zeng LH, Rensing NR, Zhang B, Gutmann DH, Gambello MJ, Wong M 2011. Tsc2 gene inactivation causes a more severe epilepsy phenotype than Tsc1 inactivation in a mouse model of tuberous sclerosis complex. Hum. Mol. Genet. 20:445–54
     [Google Scholar]
  147. 147.
    Zhang B, McDaniel SS, Rensing NR, Wong M 2013. Vigabatrin inhibits seizures and mTOR pathway activation in a mouse model of tuberous sclerosis complex. PLOS ONE 8:e57445
     [Google Scholar]
  148. 148.
    Zhang L, Bartley CM, Gong X, Hsieh LS, Lin TV et al. 2014. MEK-ERK1/2-dependent FLNA overexpression promotes abnormal dendritic patterning in tuberous sclerosis independent of mTOR. Neuron 84:78–91
     [Google Scholar]
  149. 149.
    Zhou J, Shrikhande G, Xu J, McKay RM, Burns DK et al. 2011. Tsc1 mutant neural stem/progenitor cells exhibit migration deficits and give rise to subependymal lesions in the lateral ventricle. Genes Dev 25:1595–600
     [Google Scholar]
/content/journals/10.1146/annurev-genom-083118-015354
Loading
Genetic Etiologies, Diagnosis, and Treatment of Tuberous Sclerosis Complex
Annual Review of Genomics and Human Genetics 20, 217 (2019); https://doi.org/10.1146/annurev-genom-083118-015354
/content/journals/10.1146/annurev-genom-083118-015354
/content/journals/10.1146/annurev-genom-083118-015354
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error