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EXT1

Identity

HGNC (Hugo) EXT1
Location 8q24.11-q24.13
Location_base_pair Starts at 118880783 and ends at 119193239 bp from pter ( according to hg18-Mar_2006)  [Mapping]

DNA/RNA

 
Description 11 exons, spans approximately 350 kb of genomic DNA
Transcription 3.4 kb

Protein

Description 746 amino acids, 86.304 kDa
Expression mRNA is ubiquitously expressed (also in chondrocytes), highest level of expression in liver.
Localisation endoplasmic reticulum
Function a tumour suppressor function is suggested; EXT1 is an endoplasmic reticulum (ER) resident type II transmembrane glycoprotein whose expression in cells alters the synthesis and display of cell surface heparan sulfate, and EXT1 was suggested to be involved in chain polymerization of heparan sulphate; an EXT1 homologue in Drosophila melanogaster (tout-velu, Ttv) was demonstrated to be involved in heparan sulphate proteoglycan biosynthesis controlling diffusion of an important segment polarity protein called Hedgehog (Hh)
Homology human EXT2, EXTL1, EXTL2 and EXTL3, mouse Ext1, Drosophila tout velu

Mutations

Germinal germline mutations in EXT1 are causative for hereditary multiple exostoses, a genetically heterogeneous autosomal dominant disorder; mutations include nucleotide substitutions (54%), small deletions (27%) and small insertions (16%), of which the majority is predicted to result in a truncated or non-functional protein
Somatic no somatic mutations were found in 34 sporadic and hereditary osteochondromas and secondary peripheral chondrosarcomas tested

Implicated in

Entity hereditary multiple exostoses
Prognosis the main complication in hereditary multiple exostoses is malignant transformation of an osteochondroma (exostosis) into chondrosarcoma, which is estimated to occur in 1-5% of the HME cases
Cytogenetics clonal aberrations were found at band 8q24.1 in sporadic and hereditary osteochondromas using cytogenetic analysis; loss of heterozygosity was almost exclusively found at the EXT1 locus in 5 out of 14 osteochondromas
Oncogenesis two patients with multiple osteochondromas demonstrated a germline mutation combined with loss of the remaining wild type allele in three osteochondromas, supporting the Knudson's two hit model for tumour suppressor genes in osteochondroma development; these results indicate that in cartilaginous cells of the growth plate inactivation of both copies of the EXT1-gene is required for osteochondroma formation in hereditary cases
  

External links

Nomenclature
HGNC (Hugo)EXT1   3512
Entrez_Gene (NCBI)EXT1  2131  exostoses (multiple) 1
Cards
AtlasEXT1ID212
GeneCards (Weizmann)EXT1
Ensembl (Hinxton)ENSG00000182197 [Gene_View]  EXT1 [Vega]
AceView (NCBI)EXT1
Genatlas (Paris)EXT1
euGene (Indiana)2131
SOURCE (Stanford)NM_000127
Genomic and cartography
GoldenPath (UCSC)EXT1  -     chr8:118880783-119193239 -  8q24.11   [Description]    (hg18-Mar_2006)
EnsemblEXT1 - 8q24.11 [CytoView]
Mapping of homologs : NCBIEXT1 [Mapview]
OMIM133700   150230   215300   608177   
Gene and transcription
Gene : Genbank (Entrez)AK130054 AK313129 BC001174 DQ891868 DQ895056
Reference sequence (RefSeq transcript) :SRSNM_000127
Reference transcript : EntrezNM_000127
RefSeq genomic : SRSAC_000051 AC_000140 NC_000008 NG_007455 NT_008046 NW_001839136 NW_923984
RefSeq genomic : EntrezAC_000051 AC_000140 NC_000008 NG_007455 NT_008046 NW_001839136 NW_923984
Consensus coding sequences : CCDS NCBIEXT1
Cluster EST : UnigeneHs.492618 [ SRS ] Hs.492618 [ NCBI ]
Alternative Splicing : Fast-db (Paris)8135
Protein : pattern, domain, 3D structure
Protein : UniProt/SwissProtQ16394 (SRS) Q16394 (Expasy) Q16394 (Uniprot)
With graphics : InterProQ16394
Splice isoforms : VarSplice FASTAQ16394(VarSplice FASTA)
Domains : Interpro (SRS)Exostosin    HexNAc_Trfase_a   
Domains : Interpro (EBI)Exostosin    HexNAc_Trfase_a   
Related proteins : CluSTrQ16394
Domain families : Pfam SRSExostosin (PF03016)    EXTL2 (PF09258)   
Domain families : Pfam SangerExostosin (PF03016)    EXTL2 (PF09258)   
Domain families : Pfam NCBIpfam03016    pfam09258   
Blocks (Seattle)Q16394
Crystal structure of protein : PDB SRS
Crystal structure of protein : PDBSum
Crystal structure of protein : IMB
Crystal structure of protein : PDB RSDB
HPRD00598
Protein Interaction databases
DIP (DOE-UCLA)Q16394
IntAct (EBI)Q16394
Polymorphism : SNP, mutations, diseases
Single Nucleotide Polymorphism (SNP) : dbSNP NCBIEXT1
SNP : GeneSNP UtahEXT1
SNP : HGBaseEXT1
Genetic variants : HAPMAPEXT1
Somatic Mutations in Cancer : COSMICEXT1 
Mutations and Diseases : HGMDEXT1
Hereditary diseases : OMIM133700    150230    215300    608177   
Hereditary diseases : GENETests133700    150230    215300    608177   
Diseases : Genetic AssociationEXT1
General knowledge
Homologs : HomoloGeneEXT1
Homology/Alignments : Family Browser UCSCEXT1
Phylogenetic Trees/Animal Genes : TreeFamEXT1
Catalytic activity : Enzyme2.4.1.224 [ Enzyme-Expasy ]   2.4.1.224 [ Enzyme-SRS ]   2.4.1.224 [ IntEnz-EBI ]   2.4.1.224 [ BRENDA ]   2.4.1.224 [ KEGG ]   
Chemical/Protein Interactions : CTD2131
Keywords Ontology : AmiGOGolgi membrane  skeletal system development  ossification  protein binding  endoplasmic reticulum  Golgi apparatus  glycosaminoglycan biosynthetic process  signal transduction  gastrulation  endoderm development  mesoderm development  heparan sulfate proteoglycan biosynthetic process, polysaccharide chain biosynthetic process  membrane  integral to membrane  integral to endoplasmic reticulum membrane  heparan sulfate N-acetylglucosaminyltransferase activity  protein homodimerization activity  negative regulation of cell cycle  protein heterodimerization activity  glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase activity  N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase activity  
Keywords Ontology : EGO-EBIGolgi membrane  skeletal system development  ossification  protein binding  endoplasmic reticulum  Golgi apparatus  glycosaminoglycan biosynthetic process  signal transduction  gastrulation  endoderm development  mesoderm development  heparan sulfate proteoglycan biosynthetic process, polysaccharide chain biosynthetic process  membrane  integral to membrane  integral to endoplasmic reticulum membrane  heparan sulfate N-acetylglucosaminyltransferase activity  protein homodimerization activity  negative regulation of cell cycle  protein heterodimerization activity  glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase activity  N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase activity  
Pathways : BIOCARTA
Pathways : KEGGHeparan sulfate biosynthesisGlycan structures - biosynthesis 1
Other databases
Probes
ProbeCancer Cytogenetics (Bari)
Probes : ImagenesEXT1 Related clones (RZPD - Berlin)
Literature
PubMed48 Pubmed reference(s) in Entrez
PubGeneEXT1

Bibliography

Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1).
Ahn J, Lˆºdecke HJ, Lindow S, Horton WA, Lee B, Wagner MJ, Horsthemke B, Wells DE
Nature genetics. 1995 ; 11 (2) : 137-143.
PMID 7550340
 
Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion.
Bellaiche Y, The I, Perrimon N
Nature. 1998 ; 394 (6688) : 85-88.
PMID 9665133
 
EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas.
Bovˆ©e JV, Cleton-Jansen AM, Wuyts W, Caethoven G, Taminiau AH, Bakker E, Van Hul W, Cornelisse CJ, Hogendoorn PC
American journal of human genetics. 1999 ; 65 (3) : 689-698.
PMID 10441575
 
Loss of heterozygosity and DNA ploidy point to a diverging genetic mechanism in the origin of peripheral and central chondrosarcoma.
Bovˆ©e JV, Cleton-Jansen AM, Kuipers-Dijkshoorn NJ, van den Broek LJ, Taminiau AH, Cornelisse CJ, Hogendoorn PC
Genes, chromosomes & cancer. 1999 ; 26 (3) : 237-246.
PMID 10502322
 
Clonal karyotypic abnormalities of the hereditary multiple exostoses chromosomal loci 8q24.1 (EXT1) and 11p11-12 (EXT2) in patients with sporadic and hereditary osteochondromas.
Bridge JA, Nelson M, Orndal C, Bhatia P, Neff JR
Cancer. 1998 ; 82 (9) : 1657-1663.
PMID 9576285
 
Genetic heterogeneity in families with hereditary multiple exostoses.
Cook A, Raskind W, Blanton SH, Pauli RM, Gregg RG, Francomano CA, Puffenberger E, Conrad EU, Schmale G, Schellenberg G
American journal of human genetics. 1993 ; 53 (1) : 71-79.
PMID 8317501
 
Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome II and loss of heterozygosity for EXT-linked markers on chromosomes II and 8.
Hecht JT, Hogue D, Strong LC, Hansen MF, Blanton SH, Wagner M
American journal of human genetics. 1995 ; 56 (5) : 1125-1131.
PMID 7726168
 
The tumor suppressor EXT-like gene EXTL2 encodes an alpha1, 4-N-acetylhexosaminyltransferase that transfers N-acetylgalactosamine and N-acetylglucosamine to the common glycosaminoglycan-protein linkage region. The key enzyme for the chain initiation of heparan sulfate.
Kitagawa H, Shimakawa H, Sugahara K
The Journal of biological chemistry. 1999 ; 274 (20) : 13933-13937.
PMID 10318803
 
Expression and functional analysis of mouse EXT1, a homolog of the human multiple exostoses type 1 gene.
Lin X, Gan L, Klein WH, Wells D
Biochemical and biophysical research communications. 1998 ; 248 (3) : 738-743.
PMID 9703997
 
Isolation of the mouse cDNA homologous to the human EXT1 gene responsible for Hereditary Multiple Exostoses.
Lin X, Wells D
DNA sequence : the journal of DNA sequencing and mapping. 1997 ; 7 (3-4) : 199-202.
PMID 9254013
 
The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate.
Lind T, Tufaro F, McCormick C, Lindahl U, Lidholt K
The Journal of biological chemistry. 1998 ; 273 (41) : 26265-26268.
PMID 9756849
 
The murine Ext1 gene shows a high level of sequence similarity with its human homologue and is part of a conserved linkage group on chromosome 15.
Lohmann DR, Buiting K, Lˆºdecke HJ, Horsthemke B
Cytogenetics and cell genetics. 1997 ; 76 (3-4) : 164-166.
PMID 9186511
 
Genomic organization and promoter structure of the human EXT1 gene.
Lˆºdecke HJ, Ahn J, Lin X, Hill A, Wagner MJ, Schomburg L, Horsthemke B, Wells DE
Genomics. 1997 ; 40 (2) : 351-354.
PMID 9119404
 
New perspectives on the molecular basis of hereditary bone tumours.
McCormick C, Duncan G, Tufaro F
Molecular medicine today. 1999 ; 5 (11) : 481-486.
PMID 10529789
 
The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate.
McCormick C, Leduc Y, Martindale D, Mattison K, Esford LE, Dyer AP, Tufaro F
Nature genetics. 1998 ; 19 (2) : 158-161.
PMID 9620772
 
Loss of chromosome band 8q24 in sporadic osteocartilaginous exostoses.
Mertens F, Rydholm A, Kreicbergs A, Willˆ©n H, Jonsson K, Heim S, Mitelman F, Mandahl N
Genes, chromosomes & cancer. 1994 ; 9 (1) : 8-12.
PMID 7507706
 
Loss of heterozygosity in chondrosarcomas for markers linked to hereditary multiple exostoses loci on chromosomes 8 and 11.
Raskind WH, Conrad EU, Chansky H, Matsushita M
American journal of human genetics. 1995 ; 56 (5) : 1132-1139.
PMID 7726169
 
A direct interaction between EXT proteins and glycosyltransferases is defective in hereditary multiple exostoses.
Simmons AD, Musy MM, Lopes CS, Hwang LY, Yang YP, Lovett M
Human molecular genetics. 1999 ; 8 (12) : 2155-2164.
PMID 10545594
 
Hedgehog movement is regulated through tout velu-dependent synthesis of a heparan sulfate proteoglycan.
The I, Bellaiche Y, Perrimon N
Molecular cell. 1999 ; 4 (4) : 633-639.
PMID 10549295
 
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Contributor(s)

Written01-2000Judith VMG Bovée
Updated03-2002Judith VMG Bovée

Citation

This paper should be referenced as such :
- . EXT1. Atlas Genet Cytogenet Oncol Haematol. January 2000 .
URL : http://AtlasGeneticsOncology.org/Genes/EXT1ID212.html
Bovée JVMG . EXT1. Atlas Genet Cytogenet Oncol Haematol. March 2002 .
URL : http://AtlasGeneticsOncology.org/Genes/EXT1ID212.html
Bovée JVMG . EXT1. Atlas Genet Cytogenet Oncol Haematol. .
URL : http://AtlasGeneticsOncology.org/Genes/EXT1ID212.html

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indexed on : Sat Jun 27 16:39:37 CEST 2009

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