EXT1

Identity

Hugo	EXT1
Location	8q24.11-q24.13

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
Hugo	EXT1
GDB	EXT1
Entrez_Gene	EXT1  2131  exostoses (multiple) 1
	Cards
Atlas	EXT1ID212
GeneCards	EXT1
Ensembl	EXT1 [Search_View]   ENSG00000182197 [Gene_View]
Genatlas	EXT1
GeneLynx	EXT1
eGenome	EXT1
euGene	2131
	Genomic and cartography
GoldenPath	EXT1  -     chr8:118880783-119193239 -  8q24.11-q24.13   [Description]    (hg18-Mar_2006)
Ensembl	EXT1 - 8q24.11-q24.13 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	EXT1
	Gene and transcription
Genbank	AK130054 [ ENTREZ ]
Genbank	BC001174 [ ENTREZ ]
Genbank	DQ891868 [ ENTREZ ]
Genbank	DQ895056 [ ENTREZ ]
Genbank	S79639 [ ENTREZ ]
RefSeq	NM_000127 [ SRS ]    NM_000127 [ ENTREZ ]
RefSeq	AC_000051 [ SRS ]    AC_000051 [ ENTREZ ]
RefSeq	NC_000008 [ SRS ]    NC_000008 [ ENTREZ ]
RefSeq	NT_008046 [ SRS ]    NT_008046 [ ENTREZ ]
RefSeq	NW_923984 [ SRS ]    NW_923984 [ ENTREZ ]
AceView	EXT1 AceView - NCBI
Unigene	Hs.492618 [ SRS ]    Hs.492618 [ NCBI ]     HS492618 [ spliceNest ]
Fast-db	8135 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	Q16394 [ SRS]    Q16394 [ EXPASY ]     Q16394 [ INTERPRO ]
Interpro	IPR004263 Exostosin [ SRS ]    IPR004263 Exostosin [ EBI ]
Interpro	IPR015338 HexNAc_Trfase_a [ SRS ]    IPR015338 HexNAc_Trfase_a [ EBI ]
CluSTr	Q16394
Pfam	PF03016 Exostosin [ SRS ]    PF03016 Exostosin [ Sanger ]    pfam03016 [ NCBI-CDD ]
Pfam	PF09258 EXTL2 [ SRS ]    PF09258 EXTL2 [ Sanger ]    pfam09258 [ NCBI-CDD ]
Blocks	Q16394
HPRD	00598
	Protein Interaction databases
DIP	Q16394
IntAct	Q16394
	Polymorphism : SNP, mutations, diseases
OMIM	133700;215300;608177    [ map ]
GENECLINICS	133700;215300;608177
SNP	EXT1 [dbSNP-NCBI]
SNP	NM_000127 [SNP-NCI]
SNP	EXT1 [GeneSNPs - Utah]  EXT1] [HGBASE - SRS]
HAPMAP	EXT1 [HAPMAP]
COSMIC	EXT1 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	EXT1
	General knowledge
Family Browser	EXT1 [UCSC Family Browser]
SOURCE	NM_000127
SMD	Hs.492618
SAGE	Hs.492618
Enzyme	2.4.1.224 [ Enzyme-SRS ]   2.4.1.224 [ Brenda-SRS ]   2.4.1.224 [ KEGG ]   2.4.1.224 [ WIT ]
GO	Golgi membrane [Amigo]  Golgi membrane
GO	skeletal development [Amigo]  skeletal development
GO	protein binding [Amigo]  protein binding
GO	endoplasmic reticulum [Amigo]  endoplasmic reticulum
GO	endoplasmic reticulum membrane [Amigo]  endoplasmic reticulum membrane
GO	Golgi apparatus [Amigo]  Golgi apparatus
GO	glycosaminoglycan biosynthetic process [Amigo]  glycosaminoglycan biosynthetic process
GO	cell cycle [Amigo]  cell cycle
GO	signal transduction [Amigo]  signal transduction
GO	heparan sulfate proteoglycan biosynthetic process [Amigo]  heparan sulfate proteoglycan biosynthetic process
GO	membrane [Amigo]  membrane
GO	integral to membrane [Amigo]  integral to membrane
GO	transferase activity, transferring glycosyl groups [Amigo]  transferase activity, transferring glycosyl groups
GO	integral to endoplasmic reticulum membrane [Amigo]  integral to endoplasmic reticulum membrane
GO	negative regulation of cell cycle [Amigo]  negative regulation of cell cycle
GO	glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase activity [Amigo]  glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase activity
GO	N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase activity [Amigo]  N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase activity
KEGG	Heparan sulfate biosynthesis
KEGG	Glycan structures - biosynthesis 1
PubGene	EXT1
TreeFam	EXT1
CTD	2131 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	Cancer Cytogenetics (Bari)
Probe	EXT1 Related clones (RZPD - Berlin)
	PubMed
PubMed	43 Pubmed reference(s) in LocusLink

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

REVIEW articles	automatic search in PubMed
Last year publications	automatic search in PubMed

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Contributor(s)

Written	01-2000	Judith VMG Bovée

Citation

This paper should be referenced as such :

Bovée JVMG . EXT1. Atlas Genet Cytogenet Oncol Haematol. January 2000 . URL : http://AtlasGeneticsOncology.org/Genes/EXT1ID212.html

Bovée JVMG . EXT1. Atlas Genet Cytogenet Oncol Haematol. . URL : http://AtlasGeneticsOncology.org/Genes/EXT1ID212.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Wed Jul 2 08:23:28 2008