Genetics of Tuberous Sclerosis Complex

Tuberous Sclerosis Complex: Genes, Clinical Features and Therapeutics

Volumn , Issue , 2010, Pages 27-60

  Kwiatkowski, David J ^a  

^a BRIGHAM AND WOMEN S HOSPITAL   (United States)

Author keywords

Chromosome; Exon; Hamartoma; Mosaicism; Mutation; Polymorphisms; TSC1; TSC2

Indexed keywords

EID: 84886148621     PISSN: None     EISSN: None     Source Type: Book    
DOI: 10.1002/9783527630073.ch4     Document Type: Chapter

References (112)

1. Fryer, A.E., Connor, J.M., Povey, S., Yates, J.R.W., Chalmers, A., Fraser, I., Yates, A.D., and Osborne, J.P.. (1987) Evidence that the gene for tuberous sclerosis is on chromosome 9. Lancet, 1 (8534), 659-661.
2. Northrup, H., Beaudet, A.L., O'Brien, W.E., Herman, G.E., Lewis, R.A., and Pollack, M.S.. (1987) Linkage of tuberous sclerosis to ABO blood group. Lancet, 2 (8562), 804-805.
3. Sampson, J.R., Yates, J.R.W., Pirrit, L.A., Fleury, P., Winship, I., Beighton, P., and Connor, J.M. (1989) Evidence for genetic heterogeneity in tuberous sclerosis. J. Med. Genet., 26, 511-516.
4. Janssen, L.A.J., Sandkuijl, L.A., Merkens, E.C., Maat-Kievit, J.A., Sampson, J.R., Fleury, P., Hennekam, R.C., Grosveld, G.C., Lindhout, D., and Halley, D.J. (1990) Genetic heterogeneity in tuberous sclerosis. Genomics, 8, 237-242.
5. Northrup, H., Kwiatkowski, D., Roach, E., Dobyns, W., Lewis, R., Herman, G., Rodriguez, E., Daiger, S., and Blanton, S. (1992) Evidence for genetic heterogeneity in tuberous sclerosis: one locus on chromosome 9 and at least one locus elsewhere. Am. J. Hum. Genet., 51, 709-720.
6. Sampson, J., Janssen, L., and Sandkuijl, L. (1992) Linkage investigation of three putative tuberous sclerosis determining loci on chromosomes 9q, 11q, and 12q. J. Med. Genet., 29, 861-866.
7. Kandt, R., Haines, J., Smith, M., Northrup, H., Gardner, R., Short, M., Dumars, K., Roach, E., Steingold, S., Wall, S., Blanton, S., Flodman, P., Kwiatkowski, D., Jewell, A., Weber, J., Roses, A., and Pericak-Vance, M. (1992) Linkage of a major gene locus for tuberous sclerosis to a chromosome-16 marker for polycystic kidney disease. Nat. Genet., 2, 37-41.
8. Janssen, B., Sampson, J., van der Est, M., Deelen, W., Verhoef, S., Daniels, I., Hesseling, A., Brook, C.P., Nellist, M., Lindhout, D., Sandkuijl, L., and Halley, D. (1994) Refined localization of TSC1 by combined analysis of 9q34 and 16p13 data in 14 tuberous sclerosis families. Hum. Genet., 94, 437-440.
9. Povey, S., Burley, M.W., Attwood, J., Benham, F., Hunt, D., Jeremiah, S.J., Franklin, D., Gillett, G., Malas, S., Robson, E.B., Tippett, P., Edwards, J.H., Kwiatkowski, D.J., Super, M.,Mueller, R., Fryer, A., Clarke, A., Webb, D., and Osborne, J. (1994) Two loci for tuberous sclerosis: one on 9q34 and one on 16p13. Ann. Hum. Genet., 58, 107-127.
10. Kwiatkowski, D.J., Armour, J., Bale, A.E., Fountain, J.W., Goudie, D., Haines, J.L., Knowles, M.A., Pilz, A., Slaugenhaupt, S., and Povey, S. (1993) Report and abstracts of the second international workshop on human chromosome 9 mapping 1993. Cytogenet. Cell Genet., 64, 93-121.
11. European Chromosome 16 Tuberous Sclerosis Consortium. (1993) Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell, 75, 1305-1315.
12. The European Polycystic Kidney Disease Consortium. (1994) The polycystic kidney disease 1 gene encodes a 14 kb transcript and lies within a duplicated region on chromosome 16. Cell, 77, 881-894.
13. Wilkie, A.O., Buckle, V.J., Harris, P.C., Lamb, J., Barton, N.J., Reeders, S.T., Lindenbaum, R.H., Nicholls, R.D., Barrow, M., Bethlenfalvay, N.C. et al. (1990) Clinical features and molecular analysis of the alpha thalassemia/mental retardation syndromes. I. Cases due to deletions involving chromosome band 16p13.3. Am. J. Hum. Genet., 46, 1112-1126.
14. Haines, J.L., Short, M.P., Kwiatkowski, D.J., Jewell, A., Andermann, E., Bejjani, B., Yang, C.H., Gusella, J.F., and Amos, J.A. (1991) Localization of one gene for tuberous sclerosis within 9q32-9q34, and further evidence for heterogeneity. Am. J. Hum. Genet., 49, 764-772.
15. Nellist, M., Brook-Carter, P.T., Connor, J.M., Kwiatkowski, D.J., Johnson, P., and Sampson, J.R. (1993) Identification of markers flanking the tuberous sclerosis locus on chromosome 9 (TSC1). J. Med. Genet., 30, 224-227.
16. van Slegtenhorst, M., de Hoogt, R., Hermans, C., Nellist, M., Janssen, B., Verhoef, S., Lindhout, D., van den Ouweland, A., Halley, D., Young, J., Burley, M., Jeremiah, S., Woodward, K., Nahmias, J., Fox, M., Ekong, R., Osborne, J., Wolfe, J., Povey, S., Snell, R.G., Cheadle, J.P., Jones, A.C., Tachataki, M., Ravine, D., and Kwiatkowski, D.J. (1997) Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.cience, 277, 805-808.
17. Kobayashi, T., Hirayama, Y., Kobayashi, E., Kubo, Y., and Hino, O. (1995) A germline insertion in the tuberous sclerosis (Tsc2) gene gives rise to the Eker rat model of dominantly inherited cancer. Nat. Genet., 9, 70-74.
18. Maheshwar, M.M., Sandford, R., Nellist, M., Cheadle, J.P., Sgotto, B., Vaudin, M., and Sampson, J.R. (1996) Comparative analysis and genomic structure of the tuberous sclerosis 2 (TSC2) gene in human and pufferfish. Hum. Mol. Genet., 5, 131-137.
19. Xu, L., Sterner, C., Maheshwar, M.M., Wilson, P.J., Nellist, M., Short, P.M., Haines, J.L., Sampson, J.R., and Ramesh, V. (1995) Alternative splicing of the tuberous sclerosis 2 (TSC2) gene in human and mouse tissues. Genomics, 27, 475-480.
20. Kim, K.K., Pajak, L.,Wang, H., and Field, L.J. (1995) Cloning, developmental expression, and evidence for alternative splicing of the murine tuberous sclerosis (TSC2) gene product. Cell Mol. Biol. Res., 41, 515-526.
21. Momose, S., Kobayashi, T., Mitani, H., Hirabayashi, M., Ito, K., Ueda, M., Nabeshima, Y., and Hino, O. (2002) Identification of the coding sequences responsible for Tsc2-mediated tumor suppression using a transgenic rat system. Hum. Mol. Genet., 11,2997-3006.
22. Momose, S., Kobayashi, T., Tada, N., Itoyama, S., and Hino, O. (2007) N-terminal hamartin-binding and C-terminal GAP domain of tuberin can separate in vivo. Biochem. Biophys. Res. Commun., 356, 693-698.
23. Maheshwar, M.M., Cheadle, J.P., Jones, A.C., Myring, J., Fryer, A.E., Harris, P.C., and Sampson, J.R. (1997) The GAPrelated domain of tuberin, the product of the TSC2 gene, is a target for missensemutations in tuberous sclerosis. Hum. Mol. Genet., 6, 1991-1996.
24. van Slegtenhorst, M., Nellist, M., Nagelkerken, B., Cheadle, J., Snell, R., van den Ouweland, A., Reuser, A., Sampson, J., Halley, D., and van der Sluijs, P. (1998) Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products. Hum. Mol. Genet., 7, 1053-1058.
25. Plank, T.L., Yeung, R.S., andHenske, 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.
26. Cheadle, J.P., Reeve, M.P., Sampson, J.R., and Kwiatkowski, D.J. (2000) Molecular genetic advances in tuberous sclerosis. Hum. Genet., 107, 97-114.
27. Sampson, J.R., Maheshwar, M.M., Aspinwall, R., Thompson, P., Cheadle, J.P., Ravine, D., Roy, S., Haan, E., Bernstein, J., and Harris, P.C. (1997) Renal cystic disease in tuberous sclerosis: role of the polycystic kidney disease 1 gene. Am. J. Hum. Genet., 61, 843-851.
28. Au, K.-S., Rodriguez, J.A., Finch, J.L., Volcik, K.A., Roach, E.S., Delgado, M.R., Rodriguez, E., and Northrup, H. (1998) Germ-line mutational analysis of the TSC2 gene in 90 tuberous-sclerosis patients. Am. J. Hum. Genet., 62, 286-294.
29. Young, J.M., Burley, M.W., Jeremiah, S.J., Jeganathan, D., Ekong, R., Osborne, J.P., and Povey, S. (1998) A mutation screen of the TSC1 gene reveals 26 protein truncating mutations and 1 splice site mutation in a panel of 79 tuberous sclerosis patients. Ann. Hum. Genet., 62, 203-213.
30. Zhang, H., Nanba, E., Yamamoto, T., Ninomiya, H., Ohno, K., Mizuguchi, M., and Takeshita, K. (1999) Mutational analysis of TSC1 and TSC2 genes in Japanese patients with tuberous sclerosis complex. J. Hum. Genet., 44, 391-396.
31. Mayer, K., Ballhausen,W., and Rott, H.D. (1999) Mutation screening of the entire coding regions of the TSC1 and the TSC2 gene with the protein truncation test (PTT) identifies frequent splicing defects. Hum. Mutat., 14, 401-411.
32. Niida, Y., Lawrence-smith, N., Banwell, A., Hammer, E., Lewis, J., Beauchamp, R.L., Sims, K., Ramesh, V., and Ozelius, L. (1999) Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated patients with tuberous sclerosis. Hum. Mutat., 14, 412-422.
33. Jones, A.C., Shyamsundar, M.M., Thomas, M.W.,Maynard, J., Idziaszczyk, S., Tomkins, S., Sampson, J.R., and Cheadle, J.P. (1999) Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. Am. J. Hum. Genet., 64, 1305-1315.
34. van Slegtenhorst, M., Verhoef, S., Tempelaars, A., Bakker, L., Wang, Q., Wessels, M., Bakker, R., Nellist, M., Lindhout, D., Halley, D., and van den Ouweland, A. (1999) Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosis complex patients: no evidence for genotype-phenotype correlation. J. Med. Genet., 36, 285-289.
35. Yamashita, Y., Ono, J., Okada, S.,Wataya-Kaneda, M., Yoshikawa, K., Nishizawa, M., Hirayama, Y., Kobayashi, E., Seyama, K., and Hino, O. (2000) Analysis of all exons of TSC1 and TSC2 genes for germline mutations in Japanese patients with tuberous sclerosis: report of 10 mutations. Am. J. Med. Genet., 90, 123-126.
36. Dabora, S.L., Jozwiak, S., Franz, D.N., Roberts, P.S., Nieto, A., Chung, J., Choy, Y.S., Reeve, M.P., Thiele, E., Egelhoff, J.C., Kasprzyk-Obara, J., Domanska-pakiela, D., and Kwiatkowski, D.J. (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.
37. Langkau, N., Martin, N., Brandt, R., Zugge, K., Quast, S., Wiegele, G., Jauch, A., Rehm, M., Kuhl, A., Mack-Vetter, M., Zimmerhackl, B., and Janssen, B. (2002) TSC1 and TSC2 mutations in tuberous sclerosis, the associated phenotypes and a model to explain observed TSC1/TSC2 frequency ratios. Eur. J. Pediatr., 161, 393-402.
38. Apak, A.,Haliloglu, G., Kose, G., Yilmaz, E., Anlar, B., and Aysun, S. (2003) Mutation analysis of TSC2 gene in 33 Turkish familial cases with tuberous sclerosis. Turk. J. Pediatr., 45, 1-5.
39. Rendtorff, N.D., Bjerregaard, B., Frodin, M., Kjaergaard, S., Hove, H., Skovby, F., Brondum-Nielsen, K., and Schwartz, M. (2005) Analysis of 65 tuberous sclerosis complex (TSC) patients by TSC2 DGGE, TSC1/TSC2 MLPA, and TSC1 longrange PCR sequencing, and report of 28 novel mutations. Hum. Mutat., 26, 374-383.
40. Sancak, O., Nellist, M., Goedbloed, M., Elfferich, P.,Wouters, C.,Maat-Kievit, A., Zonnenberg, B., Verhoef, S., Halley, D., and van den Ouweland, A. (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.
41. Ali, M., Girimaji, S.C., Markandaya, M., Shukla, A.K., Sacchidanand, S., and Kumar, A. (2005) Mutation and polymorphism analysis of TSC1 and TSC2 genes in Indian patients with tuberous sclerosis complex. Acta Neurol. Scand., 111, 54-63.
42. Choi, J.E., Chae, J.H., Hwang, Y.S., and Kim, K.J. (2006) Mutational analysis of TSC1 and TSC2 in Korean patients with tuberous sclerosis complex. Brain Dev., 28, 440-446.
43. Hung, C.C., Su, Y.N., Chien, S.C., Liou, H.H., Chen, C.C., Chen, P.C., Hsieh, C.J., Chen, C.P., Lee,W.T., Lin,W.L., and Lee, C.N. (2006) Molecular and clinical analyses of 84 patients with tuberous sclerosis complex. BMC Med. Genet., 7, 72.
44. Kozlowski, P., Roberts, P., Dabora, S., Franz, D., Bissler, J., Northrup, H., Au, K.S., Lazarus, R., Domanska-pakiela, D., Kotulska, K., Jozwiak, S., and Kwiatkowski, D.J. (2007) Identification of 54 large deletions/duplications in TSC1 and TSC2 using MLPA, and genotype-phenotype correlations. Hum. Genet., 121, 389-400.
45. Au, K.S., Williams, A.T., Roach, E.S., Batchelor, L., Sparagana, S.P., Delgado, M.R., Wheless, J.W., Baumgartner, J.E., Roa, B.B., Wilson, C.M., Smith-Knuppel, T.K., Cheung, M.Y., Whittemore, V.H., King, T.M., and Northrup, H. (2007) Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genet. Med., 9, 88-100.
46. Jansen, F.E., Braams, O., Vincken, K.L., Algra, A., Anbeek, P., Jennekens-Schinkel, A., Halley, D., Zonnenberg, B.A., van den Ouweland, A., van Huffelen, A.C., van Nieuwenhuizen, O., and Nellist, M. (2008) Overlapping neurologic and cognitive phenotypes in patients with TSC1 or TSC2 mutations. Neurology, 70, 908-915.
47. Zhang, M.Q. (1998) Statistical features of human exons and their flanking regions. Hum. Mol. Genet., 7, 919-932.
48. Schwarze, U., Goldstein, J.A., and Byers, P.H. (1997) Splicing defects in the COL3A1 gene: marked preference for 50 (donor) spice-site mutations in patients with exon-skipping mutations and Ehlers-Danlos syndrome type IV. Am. J. Hum. Genet., 61, 1276-1286.
49. Henikoff, S. and Henikoff, J.G. (1992) Amino acid substitution matrices from protein blocks. Proc. Natl. Acad. Sci. USA, 89, 10915-10919.
50. Nellist, M., Sancak, O., Goedbloed, M.A., Rohe, C., van Netten, D., Mayer, K., Tucker-Williams, A., van den Ouweland, A.M., and Halley, D.J. (2005) Distinct effects of single amino-acid changes to tuberin on the function of the tuberin-hamartin complex. Eur. J. Hum. Genet., 13, 59-68.
51. Nellist, M., Sancak, O., Goedbloed, M., Adriaans, A., Wessels, M., Maat-Kievit, A., Baars, M., Dommering, C., van den Ouweland, A., and Halley, D. (2008) Functional characterisation of the TSC1-TSC2 complex to assess multiple TSC2 variants identified in single families affected by tuberous sclerosis complex. BMC Med. Genet., 9, 10.
52. Cooper, D.N. and Youssoufian, H. (1988) The CpG dinucleotide and human genetic disease. Hum. Genet., 78, 151-155.
53. Jansen, F.E., Vincken, K.L., Algra, A., Anbeek, P., Braams, O., Nellist, M., Zonnenberg, B.A., Jennekens-schinkel, A., van den Ouweland, A., Halley, D., van Huffelen, A.C., and van Nieuwenhuizen, O. (2008) Cognitive impairment in tuberous sclerosis complex is a multifactorial condition. Neurology, 70, 916-923.
54. Longa, L., Saluto, A., Brusco, A., Polidoro, S., Padovan, S., Allavena, A., Carbonara, C., Grosso, E., and Migone, N. (2001) TSC1 and TSC2 deletions differ in size, preference for recombinatorial sequences, and location within the gene. Hum. Genet., 108, 156-166.
55. Nellist, M., Sancak, O., Goedbloed, M.A., van Veghel-plandsoen, M., Maat-Kievit, A., Lindhout, D., Eussen, B.H., de Klein, A., Halley, D.J., and van den Ouweland, A.M. (2005) Large deletion at the TSC1 locus in a family with tuberous sclerosis complex. Genet. Test., 9, 226-230.
56. Stenson, P.D., Ball, E., Howells, K., Phillips, A., Mort, M., and Cooper, D.N. (2008) Human gene mutation database: towards a comprehensive central mutation database. J. Med. Genet., 45, 124-126.
57. Krawczak, M., Ball, E.V., and Cooper, D.N. (1998) Neighboring-nucleotide effects on the rates of germ-line single-base-pair substitution in human genes. Am. J. Hum. Genet., 63, 474-488.
58. Ball, E.V., Stenson, P.D., Abeysinghe, S.S., Krawczak, M., Cooper, D.N., and Chuzhanova, N.A. (2005) Microdeletions and microinsertions causing human genetic disease: common mechanisms of mutagenesis and the role of local DNA sequence complexity. Hum. Mutat., 26, 205-213.
59. Verhoef, S., Bakker, L., Tempelaars, A.M., Hesseling-janssen, A.L., Mazurczak, T., Jozwiak, S., Fois, A., Bartalini, G., Zonnenberg, B.A., van Essen, A.J., Lindhout, D., Halley, D.J., and van den Ouweland, A.M. (1999) High rate of mosaicismin tuberous sclerosis complex. Am. J. Hum. Genet., 64, 1632-1637.
60. Emmerson, P., Maynard, J., Jones, S., Butler, R., Sampson, J.R., and Cheadle, J.P. (2003) Characterizing mutations in samples with low-level mosaicism by collection and analysis of DHPLC fractionated heteroduplexes. Hum. Mutat., 21, 112-115.
61. 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.
62. Roberts, P.S., Dabora, S., Thiele, E.A., Franz, D.N., Jozwiak, S., and Kwiatkowski, D.J. (2004) Somatic mosaicism is rare in unaffected parents of patients with sporadic tuberous sclerosis. J. Med. Genet., 41, e69.
63. Yates, J.R., van Bakel, I., Sepp, T., Payne, S.J.,Webb, D.W., Nevin, N.C., and Green, A.J. (1997) Female germline mosaicism in tuberous sclerosis confirmed by molecular genetic analysis. Hum. Mol. Genet., 6, 2265-2269.
64. Rose, V.M., Au, K.S., Pollom, G., Roach, E.S., Prashner, H.R., and Northrup, H. (1999) Germ-line mosaicism in tuberous sclerosis: how common? Am. J. Hum. Genet., 64, 986-992.
65. Mayer, K., Ballhausen, W., Leistner, W., and Rott, H. (2000) Three novel types of splicing aberrations in the tuberous sclerosis TSC2 gene caused by mutations apart from splice consensus sequences. Biochim. Biophys. Acta, 1502, 495-507.
66. Pymar, L.S., Platt, F.M., Askham, J.M., Morrison, E.E., and Knowles, M.A. (2008) Bladder tumour-derived somatic TSC1 missense mutations cause loss of function via distinct mechanisms. Hum. Mol. Genet., 17, 2006-2017.
67. Launonen, V. (2005) Mutations in the human LKB1/STK11 gene. Hum. Mutat., 26, 291-297.
68. Eng, C. (2003) PTEN: one gene, many syndromes. Hum. Mutat., 22, 183-198.
69. Green, A.J., Johnson, P.H., andYates, J.R. (1994) The tuberous sclerosis gene on chromosome 9q34 acts as a growth suppressor. Hum. Mol. Genet., 3, 1833-1834.
70. Henske, E.P., Scheithauer, B.W., Short, M.P., Wollmann, R., Nahmias, J., Hornigold, N., van Slegtenhorst, M., Welsh, C.T., and Kwiatkowski, D.J. (1996) Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. Am. J. Hum. Genet., 59, 400-406.
71. Au, K.S., Hebert, A.A., Roach, E.S., and Northrup, H. (1999) Complete inactivation of the TSC2 gene leads to formation of hamartomas. Am. J. Hum. Genet., 65, 1790-1795.
72. Tucker, T. and Friedman, J.M. (2002) Pathogenesis of hereditary tumors: beyond the ?two-hit? hypothesis. Clin. Genet., 62, 345-357.
73. Karbowniczek, M., Yu, J., and Henske, E.P. (2003) Renal angiomyolipomas from patients with sporadic lymphangiomyomatosis contain both neoplastic and non-neoplastic vascular structures. Am. J. Pathol., 162, 491-500.
74. Smolarek, T.A., Wessner, L.L., McCormack, F.X., Mylet, J.C., Menon, A.G., and Henske, E.P. (1998) Evidence that lymphangiomyomatosis is caused by TSC2 mutations: chromosome 16p13 loss of heterozygosity in angiomyolipomas and lymph nodes from women with lymphangiomyomatosis. Am. J. Hum. Genet., 62, 810-815.
75. Carsillo, T., Astrinidis, A., and Henske, E.P. (2000) Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc. Natl. Acad. Sci. USA, 97, 6085-6090.
76. Chan, J.A., Zhang, H., Roberts, P.S., Jozwiak, S., Wieslawa, G., Lewin-kowalik, J., Kotulska, K., and Kwiatkowski, D.J. (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.
77. Henske, E.P., Wessner, L.L., Golden, J., Scheithauer, B.W., Vortmeyer, A.O., Zhang, Z., Klein-szanto, A.J.P., Kwiatkowski, D.J., and Yeung, R.S. (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.
78. Jozwiak, S., Kwiatkowski, D., Kotulska, K., Larysz-brysz, M., Lewin-kowalik, J., Grajkowska, W., and Roszkowski, M. (2004) Tuberin and hamartin expression is reduced in the majority of subependymal giant cell astrocytomas in tuberous sclerosis complex consistent with a two-hit model of pathogenesis. J. Child Neurol., 19, 102-106.
79. Mizuguchi, M., Kato, M., Yamanouchi, H., Ikeda, K., and Takashima, S. (1996) Loss of tuberin from cerebral tissues with tuberous sclerosis and astrocytoma. Ann. Neurol., 40, 941-944 (see comments).
80. Arai, Y., Ackerley, C.A., and Becker, L.E. (1999) Loss of the TSC2 product tuberin in subependymal giant-cell tumors. Acta Neuropathol. (Berl.), 98, 233-239.
81. Ichikawa, T., Wakisaka, A., Daido, S., Takao, S., Tamiya, T., Date, I., Koizumi, S., and Niida, Y. (2005) A case of solitary subependymal giant cell astrocytoma: two somatic hits of TSC2 in the tumor, without evidence of somatic mosaicism. J. Mol. Diagn., 7, 544-549.
82. Niida, Y., Stemmer-rachamimov, A.O., Logrip, M., Tapon, D., Perez, R., Kwiatkowski, D.J., Sims, K., MacCollin, M., Louis, D.N., and Ramesh, V. (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.
83. Han, S., Santos, T.M., Puga, A., Roy, J., Thiele, E.A., McCollin, M., Stemmer-Rachamimov, A., and Ramesh, V. (2004) Phosphorylation of tuberin as a novel mechanism for somatic inactivation of the tuberous sclerosis complex proteins in brain lesions. Cancer Res., 64, 812-816.
84. Ma, L., Teruya-Feldstein, J., Bonner, P., Bernardi, R., Franz, D.N., Witte, D., Cordon-Cardo, C., and Pandolfi, P.P. (2007) Identification of S664 TSC2 phosphorylation as a marker for extracellular signal-regulated kinase mediated mTOR activation in tuberous sclerosis and human cancer. Cancer Res., 67, 7106-7112.
85. Jozwiak, J., Jozwiak, S., and Skopinski, P. (2005) Immunohistochemical and microscopic studies on giant cells in tuberous sclerosis. Histol. Histopathol., 20, 1321-1326.
86. Kotulska, K., Larysz-brysz, M., Grajkowska, W., Jozwiak, J., Wlodarski, P., Sahin, M., Lewin-kowalik, J., Domanska-pakiela, D., and Jozwiak, S.. (2009) Cardiac rhabdomyomas in tuberous sclerosis complex show apoptosis regulation and mTOR pathway abnormalities. Pediatr. Dev. Pathol., 12 (2), 89-95.
87. Hay, N. (2005) The Akt-mTOR tango and its relevance to cancer. Cancer Cell, 8, 179-183.
88. Adachi, H., Igawa, M., Shiina, H., Urakami, S., Shigeno, K., and Hino, O. (2003) Human bladder tumors with 2-hit mutations of tumor suppressor gene TSC1 and decreased expression of p27. J. Urol., 170, 601-604.
89. Takamochi, K., Ogura, T., Suzuki, K., Kawasaki, H., Kurashima, Y., Yokose, T., Ochiai, A., Nagai, K., Nishiwaki, Y., and Esumi, H. (2001) Loss of heterozygosity on chromosomes 9q and 16p in atypical adenomatous hyperplasia concomitant with adenocarcinoma of the lung. Am. J. Pathol., 159, 1941-1948.
90. Knowles, M.A., Hornigold, N., and Pitt, E. (2003) Tuberous sclerosis complex (TSC) gene involvement in sporadic tumours. Biochem. Soc. Trans., 31, 597-602.
91. 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.
92. Ehninger, D., Han, S., Shilyansky, C., Zhou, Y., Li, W., Kwiatkowski, D.J., Ramesh, V., and Silva, A.J. (2008) Reversal of learning deficits in a Tsc2 (+/-) mouse model of tuberous sclerosis. Nat. Med., 14, 843-848.
93. Mhawech-fauceglia, P., Alvarez, V., Fischer, G., Beck, A., andHerrmann, F.R. (2008) Association of TSC1/hamartin, 14-3-3sigma, and p27 expression with tumor outcomes in patients with pTa/pT1 urothelial bladder carcinoma. Am. J. Clin. Pathol., 129, 918-923.
94. Takamochi, K., Ogura, T., Yokose, T., Ochiai, A., Nagai, K., Nishiwaki, Y., Suzuki, K., and Esumi, H. (2004) Molecular analysis of the TSC1 gene in adenocarcinoma of the lung. LungCancer, 46, 271-281.
95. Jiang, W.G., Sampson, J., Martin, T.A., Lee-Jones, L., Watkins, G., Douglas-jones, A., Mokbel, K., and Mansel, R.E. (2005) Tuberin and hamartin are aberrantly expressed and linked to clinical outcome in human breast cancer: the role of promoter methylation of TSC genes. Eur. J. Cancer, 41, 1628-1636.
96. Chakraborty, S., Mohiyuddin, S.M., Gopinath, K.S., and Kumar, A. (2008) Involvement of TSC genes and differential expression of other members of the mTOR signaling pathway in oral squamous cell carcinoma. BMC Cancer, 8, 163.
97. Lu, K.H., Wu, W., Dave, B., Slomovitz, B.M., Burke, T.W., Munsell, M.F., Broaddus, R.R., and Walker, C.L. (2008) Loss of tuberous sclerosis complex-2 function and activation of mammalian target of rapamycin signaling in endometrial carcinoma. Clin. Cancer Res., 14, 2543-2550.
98. Al-Saleem, T.,Wessner, L.L., Scheithauer, B.W., Patterson, K., Roach, E.S., Dreyer, S.J., Fujikawa, K., Bjornsson, J., Bernstein, J., and Henske, E.P. (1998) Malignant tumors of the kidney, brain, and soft tissues in children and young adults with the tuberous sclerosis complex. Cancer, 83, 2208-2216.
99. Parry, L., Maynard, J.H., Patel, A., Clifford, S.C., Morrissey, C.,Maher, E.R., Cheadle, J.P., and Sampson, J.R. (2001) Analysis of the TSC1 and TSC2 genes in sporadic renal cell carcinomas. Br. J. Cancer, 85, 1226-1230.
100. Becker, A.J., Lobach, M., Klein, H., Normann, S., Nothen, M.M., von Deimling, A., Mizuguchi, M., Elger, C.E., Schramm, J., Wiestler, O.D., and Blumcke, I. (2001)Mutational analysis of TSC1 and TSC2 genes in gangliogliomas. Neuropathol. Appl. Neurobiol., 27, 105-114.
101. Przkora, R., Meyer-puttlitz, B., Schmitt, O., Berthold, F., Nothen, M., Krauss, J., Tonn, J.C., von Deimling, A., Wiestler, O.D., and Pietsch, T. (2001) Analysis of the TSC2 gene in human medulloblastoma. Acta Neuropathol. (Berl.), 102, 380-384.
102. Wienecke, R., Guha, A., Maize, J.C., Jr., Heideman, R.L., DeClue, J.E., and Gutmann, D.H. (1997) Reduced TSC2 RNA and protein in sporadic astrocytomas and ependymomas. Ann. Neurol., 42, 230-235.
103. Verhoef, S., van Diemen-Steenvoorde, R., Akkersdijk,W.L., Bax, N.M., Ariyurek, Y., Hermans, C.J., van Nieuwenhuizen, O., Nikkels, P.G., Lindhout, D., Halley, D.J., Lips, K., and van den Ouweland, A.M. (1999) Malignant pancreatic tumour within the spectrum of tuberous sclerosis complex in childhood. Eur. J. Pediatr., 158, 284-287.
104. Chung, D.C., Brown, S.B.,Graeme-cook, F., Tillotson, L.G.,Warshaw, A.L., Jensen, R.T., and Arnold, A. (1998) Localization of putative tumor suppressor loci by genome-wide allelotyping in human pancreatic endocrine tumors. Cancer Res., 58, 3706-3711.
105. Lee-Jones, L., Aligianis, I., Davies, P.A., Puga, A., Farndon, P.A., Stemmer-Rachamimov, A., Ramesh, V., and Sampson, J.R. (2004) Sacrococcygeal chordomas in patients with tuberous sclerosis complex show somatic loss of TSC1 or TSC2. Genes Chromosomes Cancer, 41, 80-85.
106. Hornick, J.L. and Fletcher, C.D. (2006) PEComa: What do we know so far? Histopathology, 48, 75-82.
107. Martignoni, G., Pea, M., Reghellin, D., Zamboni, G., and Bonetti, F. (2008) PEComas: the past, the present and the future. Virchows Arch., 452, 119-132.
108. Kenerson, H., Folpe, A.L., Takayama, T.K., and Yeung, R.S. (2007) Activation of the mTOR pathway in sporadic angiomyolipomas and other perivascular epithelioid cell neoplasms. Hum. Pathol., 38, 1361-1371.
109. Pan, C.C., Chung, M.Y., Ng, K.F., Liu, C.Y.,Wang, J.S., Chai, C.Y., Huang, S.H., Chen, P.C., and Ho, D.M. (2008) Constant allelic alteration on chromosome 16p (TSC2 gene) in perivascular epithelioid cell tumour (PEComa): genetic evidence for the relationship of PEComa with angiomyolipoma. J. Pathol., 214, 387-393.
110. Henske, E.P., Neumann, H.P., Scheithauer, B.W., Herbst, E.W., Short, M.P., and Kwiatkowski, D.J. (1995) Loss of heterozygosity in the tuberous sclerosis (TSC2) region of chromosome band 16p13 occurs in sporadic as well as TSC-associated renal angiomyolipomas. Genes Chromosomes Cancer, 13, 295-298.
111. Lee, D.F., Kuo, H.P., Chen, C.T., Hsu, J.M., Chou, C.K.,Wei, Y., Sun, H.L., Li, L.Y., Ping, B., Huang, W.C., He, X., Hung, J.Y., Lai, C.C., Ding, Q., Su, J.L., Yang, J.Y., Sahin, A.A., Hortobagyi, G.N., Tsai, F.J., Tsai, C.H., and Hung, M.C. (2007) IKK beta suppression of TSC1 links inflammation and tumor angiogenesis via the mTOR pathway. Cell, 130, 440-455.
112. Yen, C.J., Izzo, J.G., Lee, D.F., Guha, S., Wei, Y., Wu, T.T., Chen, C.T., Kuo, H.P., Hsu, J.M., Sun, H.L., Chou, C.K., Buttar, N.S.,Wang, K.K.,Huang, P.,Ajani, J., and Hung, M.C. (2008) Bile acid exposure up-regulates tuberous sclerosis complex 1/mammalian target of rapamycin pathway in Barrett?s-associated esophageal adenocarcinoma. Cancer Res., 68, 2632-2640.