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TSC1 (Tuberous Sclerosis 1)

Written2001-11Marjon van Slegtenhorst, Elizabeth Petri Henske
Fox Chase Cancer Center, 7701 Burholme Ave, Philadelphia PA 19111, USA

(Note : for Links provided by Atlas : click)

Identity

Other namesKIAA0234
HGNC (Hugo) TSC1
LocusID (NCBI) 7248
Atlas_Id 183
Location 9q34.13  [Link to chromosome band 9q34]
Location_base_pair Starts at 135766735 and ends at 135820020 bp from pter ( according to hg19-Feb_2009)  [Mapping TSC1.png]
Local_order between D9S1199 and D9S1830
Fusion genes
(updated 2016)
HLA-F-AS1 () / TSC1 (9q34.13)TSC1 (9q34.13) / CEL (9q34.2)TSC1 (9q34.13) / DOLPP1 (9q34.11)
TSC1 (9q34.13) / TSC1 (9q34.13)
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

Note
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. Renal cell carcinoma ID: 5021> develops occasionally in TSC patients.
  • Life expectancy largely depends on complications caused by the lesions in the brain and the kidneys.
  •   

    Bibliography

    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
     
    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
     
    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
     
    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
     
    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
     
    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
     
    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
     
    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
     
    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
     
    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, Hengstschläger M
    Human molecular genetics. 2000 ; 9 (12) : 1721-1727.
    PMID 10915759
     
    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
     
    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
     
    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
     
    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
     

    Citation

    This paper should be referenced as such :
    van Slegtenhorst, M ; Petri, Henske E
    TSC1 (tuberous sclerosis 1)
    Atlas Genet Cytogenet Oncol Haematol. 2002;6(1):25-26.
    Free journal version : [ pdf ]   [ DOI ]
    On line version : http://AtlasGeneticsOncology.org/Genes/TSC1ID183.html


    Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 3 ]
      Bladder: Urothelial carcinomas
    Lymphangioleiomyomatosis
    Soft Tissues: Lymphangioleiomyoma
    Soft tissue tumors: an overview

    Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 2 ]
      Familial nervous system tumour syndromes Tuberous sclerosis (TSC)

    External links

    Nomenclature
    HGNC (Hugo)TSC1   12362
    Cards
    AtlasTSC1ID183
    Entrez_Gene (NCBI)TSC1  7248  tuberous sclerosis 1
    AliasesLAM; TSC
    GeneCards (Weizmann)TSC1
    Ensembl hg19 (Hinxton)ENSG00000165699 [Gene_View]  chr9:135766735-135820020 [Contig_View]  TSC1 [Vega]
    Ensembl hg38 (Hinxton)ENSG00000165699 [Gene_View]  chr9:135766735-135820020 [Contig_View]  TSC1 [Vega]
    ICGC DataPortalENSG00000165699
    TCGA cBioPortalTSC1
    AceView (NCBI)TSC1
    Genatlas (Paris)TSC1
    WikiGenes7248
    SOURCE (Princeton)TSC1
    Genomic and cartography
    GoldenPath hg19 (UCSC)TSC1  -     chr9:135766735-135820020 -  9q34   [Description]    (hg19-Feb_2009)
    GoldenPath hg38 (UCSC)TSC1  -     9q34   [Description]    (hg38-Dec_2013)
    EnsemblTSC1 - 9q34 [CytoView hg19]  TSC1 - 9q34 [CytoView hg38]
    Mapping of homologs : NCBITSC1 [Mapview hg19]  TSC1 [Mapview hg38]
    OMIM191100   605284   606690   607341   
    Gene and transcription
    Genbank (Entrez)AA215977 AB190910 AF013168 AK297326 AK299654
    RefSeq transcript (Entrez)NM_000368 NM_001008567 NM_001162426 NM_001162427
    RefSeq genomic (Entrez)NC_000009 NC_018920 NG_012386 NT_008470 NW_004929367
    Consensus coding sequences : CCDS (NCBI)TSC1
    Cluster EST : UnigeneHs.370854 [ NCBI ]
    CGAP (NCI)Hs.370854
    Alternative Splicing GalleryENSG00000165699
    Gene ExpressionTSC1 [ NCBI-GEO ]   TSC1 [ EBI - ARRAY_EXPRESS ]   TSC1 [ SEEK ]   TSC1 [ MEM ]
    Gene Expression Viewer (FireBrowse)TSC1 [ Firebrowse - Broad ]
    SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
    GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
    BioGPS (Tissue expression)7248
    GTEX Portal (Tissue expression)TSC1
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtQ92574 (Uniprot)
    NextProtQ92574  [Sequence]  [Exons]  [Medical]  [Publications]
    With graphics : InterProQ92574
    Splice isoforms : SwissVarQ92574 (Swissvar)
    PhosPhoSitePlusQ92574
    Domains : Interpro (EBI)Hamartin   
    Domain families : Pfam (Sanger)Hamartin (PF04388)   
    Domain families : Pfam (NCBI)pfam04388   
    DMDM Disease mutations7248
    Blocks (Seattle)TSC1
    SuperfamilyQ92574
    Human Protein AtlasENSG00000165699
    Peptide AtlasQ92574
    HPRD05594
    IPIIPI00022043   IPI00922188   IPI00922672   IPI00745368   IPI00936896   IPI00921907   IPI00384490   
    Protein Interaction databases
    DIP (DOE-UCLA)Q92574
    IntAct (EBI)Q92574
    FunCoupENSG00000165699
    BioGRIDTSC1
    STRING (EMBL)TSC1
    ZODIACTSC1
    Ontologies - Pathways
    QuickGOQ92574
    Ontology : AmiGOkidney development  neural tube closure  regulation of cell-matrix adhesion  adaptive immune response  protein binding  nucleus  cytoplasm  cytosol  cytosol  actin filament  plasma membrane  plasma membrane  cell cortex  rRNA export from nucleus  regulation of translation  potassium ion transport  cell cycle arrest  cell-matrix adhesion  negative regulation of cell proliferation  adult locomotory behavior  membrane  negative regulation of macroautophagy  negative regulation of translation  hippocampus development  cerebral cortex development  lamellipodium  cell projection organization  growth cone  GTPase regulator activity  negative regulation of TOR signaling  negative regulation of TOR signaling  GTPase activating protein binding  response to insulin  TSC1-TSC2 complex  myelination  protein complex  memory T cell differentiation  regulation of phosphoprotein phosphatase activity  negative regulation of cell size  regulation of protein kinase activity  glucose import  negative regulation of insulin receptor signaling pathway  protein N-terminus binding  perinuclear region of cytoplasm  synapse organization  protein stabilization  chaperone binding  protein heterooligomerization  regulation of stress fiber assembly  regulation of cell cycle  positive regulation of focal adhesion assembly  cardiac muscle cell differentiation  activation of GTPase activity  cellular response to oxygen-glucose deprivation  regulation of neuron death  
    Ontology : EGO-EBIkidney development  neural tube closure  regulation of cell-matrix adhesion  adaptive immune response  protein binding  nucleus  cytoplasm  cytosol  cytosol  actin filament  plasma membrane  plasma membrane  cell cortex  rRNA export from nucleus  regulation of translation  potassium ion transport  cell cycle arrest  cell-matrix adhesion  negative regulation of cell proliferation  adult locomotory behavior  membrane  negative regulation of macroautophagy  negative regulation of translation  hippocampus development  cerebral cortex development  lamellipodium  cell projection organization  growth cone  GTPase regulator activity  negative regulation of TOR signaling  negative regulation of TOR signaling  GTPase activating protein binding  response to insulin  TSC1-TSC2 complex  myelination  protein complex  memory T cell differentiation  regulation of phosphoprotein phosphatase activity  negative regulation of cell size  regulation of protein kinase activity  glucose import  negative regulation of insulin receptor signaling pathway  protein N-terminus binding  perinuclear region of cytoplasm  synapse organization  protein stabilization  chaperone binding  protein heterooligomerization  regulation of stress fiber assembly  regulation of cell cycle  positive regulation of focal adhesion assembly  cardiac muscle cell differentiation  activation of GTPase activity  cellular response to oxygen-glucose deprivation  regulation of neuron death  
    Pathways : BIOCARTAmTOR Signaling Pathway [Genes]   
    Pathways : KEGGmTOR signaling pathway    PI3K-Akt signaling pathway    Insulin signaling pathway   
    REACTOMEQ92574 [protein]
    REACTOME PathwaysR-HSA-5628897 TP53 Regulates Metabolic Genes [pathway]
    REACTOME PathwaysR-HSA-165181 Inhibition of TSC complex formation by PKB [pathway]
    REACTOME PathwaysR-HSA-1632852 Macroautophagy [pathway]
    REACTOME PathwaysR-HSA-380972 Energy dependent regulation of mTOR by LKB1-AMPK [pathway]
    NDEx NetworkTSC1
    Atlas of Cancer Signalling NetworkTSC1
    Wikipedia pathwaysTSC1
    Orthology - Evolution
    OrthoDB7248
    GeneTree (enSembl)ENSG00000165699
    Phylogenetic Trees/Animal Genes : TreeFamTSC1
    Homologs : HomoloGeneTSC1
    Homology/Alignments : Family Browser (UCSC)TSC1
    Gene fusions - Rearrangements
    Fusion : MitelmanTSC1/CEL [9q34.13/9q34.2]  
    Fusion : MitelmanTSC1/DOLPP1 [9q34.13/9q34.11]  [t(9;9)(q34;q34)]  
    Fusion: TCGATSC1 9q34.13 CEL 9q34.2 PRAD
    Fusion: TCGATSC1 9q34.13 DOLPP1 9q34.11 HNSC
    Polymorphisms : SNP, variants
    NCBI Variation ViewerTSC1 [hg38]
    dbSNP Single Nucleotide Polymorphism (NCBI)TSC1
    dbVarTSC1
    ClinVarTSC1
    1000_GenomesTSC1 
    Exome Variant ServerTSC1
    ExAC (Exome Aggregation Consortium)TSC1 (select the gene name)
    Genetic variants : HAPMAP7248
    Genomic Variants (DGV)TSC1 [DGVbeta]
    Mutations
    ICGC Data PortalTSC1 
    TCGA Data PortalTSC1 
    Broad Tumor PortalTSC1
    OASIS PortalTSC1 [ Somatic mutations - Copy number]
    Cancer Gene: CensusTSC1 
    Somatic Mutations in Cancer : COSMICTSC1 
    intOGen PortalTSC1
    LOVD (Leiden Open Variation Database)Whole genome datasets
    LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
    LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
    LOVD (Leiden Open Variation Database)Tuberous sclerosis database
    BioMutasearch TSC1
    DgiDB (Drug Gene Interaction Database)TSC1
    DoCM (Curated mutations)TSC1 (select the gene name)
    CIViC (Clinical Interpretations of Variants in Cancer)TSC1 (select a term)
    intoGenTSC1
    Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
    Diseases
    DECIPHER (Syndromes)9:135766735-135820020  ENSG00000165699
    CONAN: Copy Number AnalysisTSC1 
    Mutations and Diseases : HGMDTSC1
    OMIM191100    605284    606690    607341   
    MedgenTSC1
    Genetic Testing Registry TSC1
    NextProtQ92574 [Medical]
    TSGene7248
    GENETestsTSC1
    Huge Navigator TSC1 [HugePedia]
    snp3D : Map Gene to Disease7248
    BioCentury BCIQTSC1
    ClinGenTSC1 (curated)
    Clinical trials, drugs, therapy
    Chemical/Protein Interactions : CTD7248
    Chemical/Pharm GKB GenePA37034
    Drug Sensitivity TSC1
    Clinical trialTSC1
    Miscellaneous
    canSAR (ICR)TSC1 (select the gene name)
    Other databasehttp://cancergenome.broadinstitute.org/index.php?tgene=TSC1
    Probes
    Litterature
    PubMed186 Pubmed reference(s) in Entrez
    GeneRIFsGene References Into Functions (Entrez)
    CoreMineTSC1
    EVEXTSC1
    GoPubMedTSC1
    iHOPTSC1
    REVIEW articlesautomatic search in PubMed
    Last year publicationsautomatic search in PubMed

    Search in all EBI   NCBI

    © Atlas of Genetics and Cytogenetics in Oncology and Haematology
    indexed on : Wed Sep 28 15:51:32 CEST 2016

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