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TSC1 (Tuberous Sclerosis 1)

Identity

Other namesKIAA0234
HGNC (Hugo) TSC1
Location 9q34
Location_base_pair Starts at 134756557 and ends at 134809841 bp from pter ( according to hg18-Mar_2006)  [Mapping]
Local_order between D9S1199 and D9S1830
Note tumor-suppressor

DNA/RNA

Description 23 exons, of which 21 are coding; start codon is in exon 3. Different splice variants in the 5'UTR
Transcription 1 major detected transcript at 8.6 kb, 2 additional transcripts at 4 and 2.5 kb respectively; open reading frame : 3492 bp

Protein

Note called hamartin
Description 1164 amino acids, 130 kDa; C-terminal coiled-coil domain (amino acids 730 to 965)
Expression housekeeping
Localisation cytoplasmic localisation
Function binds to ezrin, member of the ERM (ezrin-moesin-radixin) actin binding proteins
Homology no strong matches with vertebrate proteins

Mutations

Germinal germline mutations cause tuberous sclerosis, known as a multiple hamartoma syndrome, autosomal dominant pattern of inheritance. Mutations are inactivating by protein truncation, no missense mutations documented. Some cases of germline mosaicism

Implicated in

Entity Tuberous Sclerosis
Note Classified as one of the phakomatosis, a group of disorders which also includes neurofibromatosis type 1 and neurofibromatosis type 2, von Hippel-Lindau disease and Sturge-Weber syndrome
Disease Growth of a variety of benign tumors (hamartomas) in multiple organs. Disease is clinically variable. Organs most frequently involved are the heart, skin, brain, lung and kidneys.
Prognosis
  • Lesions in the brain are associated with severe manifestations of TSC. Seizures occur in about 85% of the patients and they often start in the first year of life. About 50% of the children with seizures develop mental retardation. In the second and third decade of life, renal problems are found in the majority of TSC patients. Most characteristic renal abnormalities are cysts and angiomyolipomas. PROGNOSIS
  • Renal cell carcinoma develops occasionally in TSC patients.
  • Life expectancy largely depends on complications caused by the lesions in the brain and the kidneys.
  •   

    External links

    Nomenclature
    HGNC (Hugo)TSC1   12362
    Entrez_Gene (NCBI)TSC1  7248  tuberous sclerosis 1
    Cards
    AtlasTSC1ID183
    GeneCards (Weizmann)TSC1
    Ensembl (Hinxton)ENSG00000165699 [Gene_View]  TSC1 [Vega]
    AceView (NCBI)TSC1
    Genatlas (Paris)TSC1
    euGene (Indiana)7248
    SOURCE (Stanford)NM_000368 NM_001008567 NM_001162426 NM_001162427
    Gene Expression (Array Express) ENSG00000165699
    Genomic and cartography
    GoldenPath (UCSC)TSC1  -  9q34   chr9:134756557-134809841 -  9q34   [Description]    (hg18-Mar_2006)
    EnsemblTSC1 - 9q34 [CytoView]
    Mapping of homologs : NCBITSC1 [Mapview]
    OMIM191100   605284   606690   607341   
    Gene and transcription
    Gene : Genbank (Entrez)AA215977 AB190910 AF013168 AK297326 AK299654
    Reference sequence (RefSeq transcript) :SRSNM_000368 NM_001008567 NM_001162426 NM_001162427
    Reference transcript : EntrezNM_000368 NM_001008567 NM_001162426 NM_001162427
    RefSeq genomic : SRSAC_000052 AC_000141 NC_000009 NG_012386 NT_035014 NW_001839241 NW_924573
    RefSeq genomic : EntrezAC_000052 AC_000141 NC_000009 NG_012386 NT_035014 NW_001839241 NW_924573
    Consensus coding sequences : CCDS NCBITSC1
    Cluster EST : UnigeneHs.370854 [ SRS ] Hs.370854 [ NCBI ]
    Alternative Splicing : Fast-db (Paris)16309
    Protein : pattern, domain, 3D structure
    Protein : UniProt/SwissProtQ92574 (SRS) Q92574 (Expasy) Q92574 (Uniprot)
    With graphics : InterProQ92574
    Splice isoforms : VarSplice FASTAQ92574(VarSplice FASTA)
    Domains : Interpro (SRS)Hamartin   
    Domains : Interpro (EBI)Hamartin   
    Related proteins : CluSTrQ92574
    Domain families : Pfam SRSHamartin (PF04388)   
    Domain families : Pfam SangerHamartin (PF04388)   
    Domain families : Pfam NCBIpfam04388   
    Blocks (Seattle)Q92574
    Crystal structure of protein : PDB SRS
    Crystal structure of protein : PDBSum
    Crystal structure of protein : IMB
    Crystal structure of protein : PDB RSDB
    HPRD05594
    Protein Interaction databases
    DIP (DOE-UCLA)Q92574
    IntAct (EBI)Q92574
    Polymorphism : SNP, mutations, diseases
    Single Nucleotide Polymorphism (SNP) : dbSNP NCBITSC1
    SNP : GeneSNP UtahTSC1
    SNP : HGBaseTSC1
    Genetic variants : HAPMAPTSC1
    Cancer Gene: CensusTSC1 
    Somatic Mutations in Cancer : COSMICTSC1 
    Mutations and Diseases : HGMDTSC1
    Hereditary diseases : OMIM191100    605284    606690    607341   
    Hereditary diseases : GENETests191100    605284    606690    607341   
    Diseases : Genetic AssociationTSC1
    General knowledge
    Homologs : HomoloGeneTSC1
    Homology/Alignments : Family Browser UCSCTSC1
    Phylogenetic Trees/Animal Genes : TreeFamTSC1
    Chemical/Protein Interactions : CTD7248
    Keywords Ontology : AmiGOkidney development  neural tube closure  membrane fraction  cytoplasm  microsome  cytosol  cytosol  actin filament  cell cortex  rRNA export from nucleus  potassium ion transport  nervous system development  negative regulation of cell proliferation  embryonic development  membrane  negative regulation of translation  extrinsic to membrane  hippocampus development  cerebral cortex development  lamellipodium  cell projection organization  growth cone  GTPase regulator activity  negative regulation of protein ubiquitination  negative regulation of TOR signaling pathway  GTPase activating protein binding  activation of Rho GTPase activity  response to insulin stimulus  regulation of actin cytoskeleton organization  TSC1-TSC2 complex  myelination  regulation of phosphoprotein phosphatase activity  negative regulation of cell size  regulation of protein kinase activity  protein N-terminus binding  synapse organization  chaperone binding  protein heterooligomerization  regulation of stress fiber assembly  positive regulation of focal adhesion assembly  cardiac muscle cell differentiation  
    Keywords Ontology : EGO-EBIkidney development  neural tube closure  membrane fraction  cytoplasm  microsome  cytosol  cytosol  actin filament  cell cortex  rRNA export from nucleus  potassium ion transport  nervous system development  negative regulation of cell proliferation  embryonic development  membrane  negative regulation of translation  extrinsic to membrane  hippocampus development  cerebral cortex development  lamellipodium  cell projection organization  growth cone  GTPase regulator activity  negative regulation of protein ubiquitination  negative regulation of TOR signaling pathway  GTPase activating protein binding  activation of Rho GTPase activity  response to insulin stimulus  regulation of actin cytoskeleton organization  TSC1-TSC2 complex  myelination  regulation of phosphoprotein phosphatase activity  negative regulation of cell size  regulation of protein kinase activity  protein N-terminus binding  synapse organization  chaperone binding  protein heterooligomerization  regulation of stress fiber assembly  positive regulation of focal adhesion assembly  cardiac muscle cell differentiation  
    Pathways : BIOCARTAmTOR Signaling Pathway [Genes]   
    Pathways : KEGGmTOR signaling pathwayInsulin signaling pathway
    Other databases
    Probes
    Probes : ImagenesTSC1 Related clones (RZPD - Berlin)
    Literature
    PubMed113 Pubmed reference(s) in Entrez
    PubGeneTSC1

    Bibliography

    Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34.
    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 RG, Cheadle JP, Jones AC, Tachataki M, Ravine D, Sampson JR, Reeve MP, Richardson P, Wilmer F, Munro C, Hawkins TL, Sepp T, Ali JB, Ward S, Green AJ, Yates JR, Kwiatkowska J, Henske EP, Short MP, Haines JH, Jozwiak S, Kwiatkowski DJ
    Science (New York, N.Y.). 1997 ; 277 (5327) : 805-808.
    PMID 9242607
     
    Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products.
    van Slegtenhorst M, Nellist M, Nagelkerken B, Cheadle J, Snell R, van den Ouweland A, Reuser A, Sampson J, Halley D, van der Sluijs P
    Human molecular genetics. 1998 ; 7 (6) : 1053-1057.
    PMID 9580671
     
    Hamartin, the product of the tuberous sclerosis 1 (TSC1) gene, interacts with tuberin and appears to be localized to cytoplasmic vesicles.
    Plank TL, Yeung RS, Henske EP
    Cancer research. 1998 ; 58 (21) : 4766-4770.
    PMID 9809973
     
    Mutational spectrum of the TSC1 gene in a cohort of 225 tuberous sclerosis complex patients: no evidence for genotype-phenotype correlation.
    van Slegtenhorst M, Verhoef S, Tempelaars A, Bakker L, Wang Q, Wessels M, Bakker R, Nellist M, Lindhout D, Halley D, van den Ouweland A
    Journal of medical genetics. 1999 ; 36 (4) : 285-289.
    PMID 10227394
     
    Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis.
    Jones AC, Shyamsundar MM, Thomas MW, Maynard J, Idziaszczyk S, Tomkins S, Sampson JR, Cheadle JP
    American journal of human genetics. 1999 ; 64 (5) : 1305-1315.
    PMID 10205261
     
    Characterization of the cytosolic tuberin-hamartin complex. Tuberin is a cytosolic chaperone for hamartin.
    Nellist M, van Slegtenhorst MA, Goedbloed M, van den Ouweland AM, Halley DJ, van der Sluijs P
    The Journal of biological chemistry. 1999 ; 274 (50) : 35647-35652.
    PMID 10585443
     
    The expression of hamartin, the product of the TSC1 gene, in normal human tissues and in TSC1- and TSC2-linked angiomyolipomas.
    Plank TL, Logginidou H, Klein-Szanto A, Henske EP
    Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 1999 ; 12 (5) : 539-545.
    PMID 10349994
     
    The tuberous sclerosis-1 (TSC1) gene product hamartin suppresses cell growth and augments the expression of the TSC2 product tuberin by inhibiting its ubiquitination.
    Benvenuto G, Li S, Brown SJ, Braverman R, Vass WC, Cheadle JP, Halley DJ, Sampson JR, Wienecke R, DeClue JE
    Oncogene. 2000 ; 19 (54) : 6306-6316.
    PMID 11175345
     
    Genomic organization and comparative analysis of the mouse tuberous sclerosis 1 (Tsc1) locus.
    Cheadle JP, Dobbie L, Idziaszczyk S, Hodges AK, Smith AJ, Sampson JR, Young J
    Mammalian genome : official journal of the International Mammalian Genome Society. 2000 ; 11 (12) : 1135-1138.
    PMID 11130985
     
    The TSC1 tumour suppressor hamartin regulates cell adhesion through ERM proteins and the GTPase Rho.
    Lamb RF, Roy C, Diefenbach TJ, Vinters HV, Johnson MW, Jay DG, Hall A
    Nature cell biology. 2000 ; 2 (5) : 281-287.
    PMID 10806479
     
    The TSC1 gene product, hamartin, negatively regulates cell proliferation.
    Miloloza A, Rosner M, Nellist M, Halley D, Bernaschek G, Hengstschlˆ§ger M
    Human molecular genetics. 2000 ; 9 (12) : 1721-1727.
    PMID 10915759
     
    Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia.
    Hendy GN, D'Souza-Li L, Yang B, Canaff L, Cole DE
    Human mutation. 2000 ; 16 (4) : 281-296.
    PMID 11013439
     
    Tuberin phosphorylation regulates its interaction with hamartin. Two proteins involved in tuberous sclerosis.
    Aicher LD, Campbell JS, Yeung RS
    The Journal of biological chemistry. 2001 ; 276 (24) : 21017-21021.
    PMID 11290735
     
    Hamartin expression and interaction with tuberin in tumor cell lines and primary cultures.
    Catania MG, Johnson MW, Liau LM, Kremen TJ, deVellis JS, Vinters HV
    Journal of neuroscience research. 2001 ; 63 (3) : 276-283.
    PMID 11170177
     
    Hamartin and tuberin interaction with the G2/M cyclin-dependent kinase CDK1 and its regulatory cyclins A and B.
    Catania MG, Mischel PS, Vinters HV
    Journal of neuropathology and experimental neurology. 2001 ; 60 (7) : 711-723.
    PMID 11444800
     
    Mutational analysis in a cohort of 224 tuberous sclerosis patients indicates increased severity of TSC2, compared with TSC1, disease in multiple organs.
    Dabora SL, Jozwiak S, Franz DN, Roberts PS, Nieto A, Chung J, Choy YS, Reeve MP, Thiele E, Egelhoff JC, Kasprzyk-Obara J, Domanska-Pakiela D, Kwiatkowski DJ
    American journal of human genetics. 2001 ; 68 (1) : 64-80.
    PMID 11112665
     
    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.
    Kobayashi T, Minowa O, Sugitani Y, Takai S, Mitani H, Kobayashi E, Noda T, Hino O
    Proceedings of the National Academy of Sciences of the United States of America. 2001 ; 98 (15) : 8762-8767.
    PMID 11438694
     
    Hamartin and tuberin expression in human tissues.
    Johnson MW, Kerfoot C, Bushnell T, Li M, Vinters HV
    Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2001 ; 14 (3) : 202-210.
    PMID 11266527
     
    Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size.
    Potter CJ, Huang H, Xu T
    Cell. 2001 ; 105 (3) : 357-368.
    PMID 11348592
     
    The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation.
    Tapon N, Ito N, Dickson BJ, Treisman JE, Hariharan IK
    Cell. 2001 ; 105 (3) : 345-355.
    PMID 11348591
     
    REVIEW articlesautomatic search in PubMed
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    Contributor(s)

    Written11-2001Marjon van Slegtenhorst and Elizabeth Petri Henske
    Fox Chase Cancer Center, 7701 Burholme Ave, Philadelphia PA 19111, USA

    Citation

    This paper should be referenced as such :
    van Slegtenhorst M, Petri Henske E . TSC1 (Tuberous Sclerosis 1). Atlas Genet Cytogenet Oncol Haematol. November 2001 .
    URL : http://AtlasGeneticsOncology.org/Genes/TSC1ID183.html

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Sat Feb 27 10:47:51 CET 2010

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