EXT2 (gene)

EXT2
Identifiers
Aliases	EXT2, SOTV, SSMS, exostosin glycosyltransferase 2
External IDs	OMIM: 608210; MGI: 108050; HomoloGene: 345; GeneCards: EXT2; OMA:EXT2 - orthologs
Gene location (Human) Chr. Chromosome 11 (human) Band 11p11.2 Start 44,095,648 bp End 44,251,962 bp
Gene location (Mouse) Chr. Chromosome 2 (mouse) Band 2 E1|2 51.62 cM Start 93,491,373 bp End 93,652,913 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in stromal cell of endometrium cartilage tissue smooth muscle tissue tibia islet of Langerhans body of uterus thoracic aorta right coronary artery ascending aorta Descending thoracic aorta Top expressed in tail of embryo calvaria yolk sac vestibular sensory epithelium decidua genital tubercle ankle right kidney gastrula molar More reference expression data BioGPS More reference expression data
Gene ontology Molecular function transferase activity heparan sulfate N-acetylglucosaminyltransferase activity acetylglucosaminyltransferase activity protein homodimerization activity glycosyltransferase activity N-acetylglucosaminyl-proteoglycan 4-beta-glucuronosyltransferase activity glucuronosyltransferase activity glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase activity metal ion binding protein heterodimerization activity protein binding Cellular component integral component of membrane endoplasmic reticulum membrane membrane Golgi membrane UDP-N-acetylglucosamine transferase complex endoplasmic reticulum extracellular exosome Golgi apparatus Biological process heparan sulfate proteoglycan biosynthetic process, polysaccharide chain biosynthetic process cell differentiation ossification mesoderm formation heparan sulfate proteoglycan biosynthetic process protein glycosylation glycosaminoglycan biosynthetic process cellular polysaccharide biosynthetic process signal transduction Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2132 14043 Ensembl ENSG00000151348 ENSMUSG00000027198 UniProt Q93063 P70428 RefSeq (mRNA) NM_000401 NM_001178083 NM_207122 NM_001389628 NM_001389630 NM_010163 NM_001355075 NM_001355076 RefSeq (protein) NP_000392 NP_001171554 NP_997005 NP_034293 NP_001342004 NP_001342005 Location (UCSC) Chr 11: 44.1 – 44.25 Mb Chr 2: 93.49 – 93.65 Mb PubMed search
Wikidata
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Exostosin glycosyltransferase-2 is a protein that in humans is encoded by the EXT2 gene.

This gene encodes one of two glycosyltransferases involved in the chain elongation step of heparan sulfate biosynthesis. Mutations in this gene cause the type II form of Hereditary Multiple Exostoses (HME).

Gene location

The EXT2 gene is located on chromosome 11 in the human genome, its location is on the p arm of this chromosome. The p arm of a chromosome is the shorter arm of a chromosome.

Interactions

Included in the EXT family are EXT2, EXT1, EXTL1, EXTL2, and EXTL3. The proteins formed by these genes work together to form and extend heparan sulfate chains. Heparan sulfate chains are proteoglycans present in the extracellular matrix of most tissue types. There is a lot about its function that is not entirely understood, however it is known that they have an important role for bone and cartilage formation. Cartilage is located at the growth plates of long bones and is placed in a specific pattern before it is later ossified into bone when it grows further away from the growth plate. New cartilage in a growing bone is placed through signaling proteins which bind to the heparan sulfate chains. EXT2 (protein) has also been shown to interact with TRAP1, a heat shock protein. Heat shock proteins will bind to specific proteins to help them keep their shape when the cell is stressed. TRAP1 has been found to bind to a region (in the c-terminal end) of EXT1 and EXT2 proteins to help it keep its desired shape and function.

Species Distribution

This gene was found to be present in many species other than humans such as mice, chickens, dogs, cows and many more. Other orthologs have been found including Drosophila melanogaster and Caenorhabditis elegans.

Mutations

Mutations that change the amino acid sequence of the exostosin glycosyltransferase-2 protein can lead to it becoming unfunctional. When this protein is unfunctional it causes the heparan sulfate chains to become shorter. The chains are still formed and extended by the other proteins encoded by the EXT family genes, although not to the same extent. This increases the likelihood that a cartilage cell will be placed incorrectly, as heparan sulfate is a bone and cartilage tumor suppressor. Since bone has a very specific structure, misplacing a cartilage cell in early growth is comparable to misplacement of a brick early on in construction of a wall. Misplacement in cartilage will result in cartilage tumor or tumors at the growth plates of long bones. This condition is known as hereditary multiple exostoses (HME) or hereditary multiple osteochondromas (HMO). HME can also be the result of a mutation to the EXT1 gene or other EXT family genes. EXT1 mutations tend to be more severe with more exostoses and are the cause of 56-78% of human HME cases, except for in China where mutations of the EXT2 gene are more common. HME effects 1 in 50,000 people and is more commonly seen in males in a 1.5:1 ratio.

Heredity of the EXT2 Gene

EXT2 gene mutations are dominant autosomal (not sex-linked) and is lethal in the homozygous form. This means that if the mutated gene is inherited from both parents giving the offspring two copies of the mutated gene (the homozygous form of the mutant gene) this will result in early embryonic death in the gastrula stage of development. Reasons for why this happens is that heparan sulfate has more roles than just bone formation, it also plays a role in embryonic development. Heparan sulfate can bind signaling molecules used in development such as transforming growth factor β, Fgf proteins and Wnt proteins. The only individuals with this mutation exist in the heterozygous form, this means that they have one EXT2 gene that is normal and one that is mutated. For the inheritance of this gene mutation, for a mutated parent and a not mutated parent there is a 50% chance that the offspring will also have an EXT2 mutation. For two parents with the EXT2 mutation, of their living offspring 2 out of 3 will have the mutation.

Further reading

• Wuyts W, Van Hul W (2000). "Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes". Human Mutation. 15 (3): 220–7. doi:10.1002/(SICI)1098-1004(200003)15:3<220::AID-HUMU2>3.0.CO;2-K. PMID 10679937. S2CID 45999816.
• Wuyts W, Ramlakhan S, Van Hul W, Hecht JT, van den Ouweland AM, Raskind WH, et al. (August 1995). "Refinement of the multiple exostoses locus (EXT2) to a 3-cM interval on chromosome 11". American Journal of Human Genetics. 57 (2): 382–7. PMC 1801560. PMID 7668264.
• Stickens D, Clines G, Burbee D, Ramos P, Thomas S, Hogue D, et al. (September 1996). "The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes". Nature Genetics. 14 (1): 25–32. doi:10.1038/ng0996-25. PMID 8782816. S2CID 27148572.
• Wuyts W, Van Hul W, Wauters J, Nemtsova M, Reyniers E, Van Hul EV, et al. (October 1996). "Positional cloning of a gene involved in hereditary multiple exostoses". Human Molecular Genetics. 5 (10): 1547–57. doi:10.1093/hmg/5.10.1547. PMID 8894688.
• Clines GA, Ashley JA, Shah S, Lovett M (April 1997). "The structure of the human multiple exostoses 2 gene and characterization of homologs in mouse and Caenorhabditis elegans". Genome Research. 7 (4): 359–67. doi:10.1101/gr.7.4.359. PMC 139145. PMID 9110175.
• Philippe C, Porter DE, Emerton ME, Wells DE, Simpson AH, Monaco AP (September 1997). "Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses". American Journal of Human Genetics. 61 (3): 520–8. doi:10.1086/515505. PMC 1715939. PMID 9326317.
• Wuyts W, Van Hul W, De Boulle K, Hendrickx J, Bakker E, Vanhoenacker F, et al. (February 1998). "Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses". American Journal of Human Genetics. 62 (2): 346–54. doi:10.1086/301726. PMC 1376901. PMID 9463333.
• McCormick C, Leduc Y, Martindale D, Mattison K, Esford LE, Dyer AP, Tufaro F (June 1998). "The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate". Nature Genetics. 19 (2): 158–61. doi:10.1038/514. PMID 9620772. S2CID 25832441.
• Lind T, Tufaro F, McCormick C, Lindahl U, Lidholt K (October 1998). "The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate". The Journal of Biological Chemistry. 273 (41): 26265–8. doi:10.1074/jbc.273.41.26265. PMID 9756849.
• Park KJ, Shin KH, Ku JL, Cho TJ, Lee SH, Choi IH, et al. (1999). "Germline mutations in the EXT1 and EXT2 genes in Korean patients with hereditary multiple exostoses". Journal of Human Genetics. 44 (4): 230–4. doi:10.1007/s100380050149. PMID 10429361.
• Xu L, Xia J, Jiang H, Zhou J, Li H, Wang D, et al. (1999). "Mutation analysis of hereditary multiple exostoses in the Chinese". Human Genetics. 105 (1–2): 45–50. doi:10.1007/s004390051062. PMID 10480354.
• Simmons AD, Musy MM, Lopes CS, Hwang LY, Yang YP, Lovett M (November 1999). "A direct interaction between EXT proteins and glycosyltransferases is defective in hereditary multiple exostoses". Human Molecular Genetics. 8 (12): 2155–64. doi:10.1093/hmg/8.12.2155. PMID 10545594.
• McCormick C, Duncan G, Goutsos KT, Tufaro F (January 2000). "The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate". Proceedings of the National Academy of Sciences of the United States of America. 97 (2): 668–73. Bibcode:2000PNAS...97..668M. doi:10.1073/pnas.97.2.668. PMC 15388. PMID 10639137.
• Kobayashi S, Morimoto K, Shimizu T, Takahashi M, Kurosawa H, Shirasawa T (February 2000). "Association of EXT1 and EXT2, hereditary multiple exostoses gene products, in Golgi apparatus". Biochemical and Biophysical Research Communications. 268 (3): 860–7. doi:10.1006/bbrc.2000.2219. PMID 10679296.
• Shi YR, Wu JY, Tsai FJ, Lee CC, Tsai CH (April 2000). "An R223P mutation in EXT2 gene causes hereditary multiple exostoses". Human Mutation. 15 (4): 390–1. doi:10.1002/(SICI)1098-1004(200004)15:4<390::AID-HUMU35>3.0.CO;2-E. PMID 10738008. S2CID 83566600.
• Stickens D, Brown D, Evans GA (July 2000). "EXT genes are differentially expressed in bone and cartilage during mouse embryogenesis". Developmental Dynamics. 218 (3): 452–64. doi:10.1002/1097-0177(200007)218:3<452::AID-DVDY1000>3.0.CO;2-P. PMID 10878610. S2CID 25986105.
• Bernard MA, Hall CE, Hogue DA, Cole WG, Scott A, Snuggs MB, et al. (February 2001). "Diminished levels of the putative tumor suppressor proteins EXT1 and EXT2 in exostosis chondrocytes". Cell Motility and the Cytoskeleton. 48 (2): 149–62. doi:10.1002/1097-0169(200102)48:2<149::AID-CM1005>3.0.CO;2-3. PMID 11169766.

External links

• Multiple Hereditary Exostoses Research Foundation