EXT2 (gene)

Exostosin glycosyltransferase-2 is a protein that in humans is encoded by the EXT2 gene.[5][6][7]

EXT2
Identifiers
AliasesEXT2, SOTV, SSMS, exostosin glycosyltransferase 2
External IDsOMIM: 608210 MGI: 108050 HomoloGene: 345 GeneCards: EXT2
Gene location (Human)
Chr.Chromosome 11 (human)[1]
Band11p11.2Start44,095,673 bp[1]
End44,251,981 bp[1]
RNA expression pattern


More reference expression data
Orthologs
SpeciesHumanMouse
Entrez

2132

14043

Ensembl

ENSG00000151348

ENSMUSG00000027198

UniProt

Q93063

P70428

RefSeq (mRNA)

NM_000401
NM_001178083
NM_207122

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 MbChr 2: 93.66 – 93.82 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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).[7]

Gene location

The EXT2 gene is located on chromosome 11 in the human genome, its location is on the p arm of this chromosome.[8] The p arm of a chromosome is the shorter arm of a chromosome.[9]

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.[10] 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.[11] EXT2 (protein) has also been shown to interact with TRAP1, a heat shock protein.[12] Heat shock proteins will bind to specific proteins to help them keep their shape when the cell is stressed.[13] 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.[14]

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.[15]

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).[16] HME can also be the result of a mutation to the EXT1 gene or other EXT family genes.[17] 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.[18]

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.[19]

References
  1. GRCh38: Ensembl release 89: ENSG00000151348 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000027198 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Wu YQ, Heutink P, de Vries BB, Sandkuijl LA, van den Ouweland AM, Niermeijer MF, et al. (January 1994). "Assignment of a second locus for multiple exostoses to the pericentromeric region of chromosome 11". Human Molecular Genetics. 3 (1): 167–71. doi:10.1093/hmg/3.1.167. PMID 8162019.
  6. Bridge JA, Nelson M, Orndal C, Bhatia P, Neff JR (May 1998). "Clonal karyotypic abnormalities of the hereditary multiple exostoses chromosomal loci 8q24.1 (EXT1) and 11p11-12 (EXT2) in patients with sporadic and hereditary osteochondromas". Cancer. 82 (9): 1657–63. doi:10.1002/(SICI)1097-0142(19980501)82:9<1657::AID-CNCR10>3.0.CO;2-3. PMID 9576285.
  7. "Entrez Gene: EXT2 exostoses (multiple) 2".
  8. "EXT2 exostosin glycosyltransferase 2 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. NCBI. Retrieved 14 November 2019.
  9. "How do geneticists indicate the location of a gene?". Genetics Home Reference. NIH US Library of Medicine. Retrieved 14 November 2019.
  10. Busse M, Feta A, Presto J, Wilén M, Grønning M, Kjellén L, Kusche-Gullberg M (November 2007). "Contribution of EXT1, EXT2, and EXTL3 to heparan sulfate chain elongation". The Journal of Biological Chemistry. 282 (45): 32802–10. doi:10.1074/jbc.M703560200. PMID 17761672.
  11. Huegel J, Sgariglia F, Enomoto-Iwamoto M, Koyama E, Dormans JP, Pacifici M (September 2013). "Heparan sulfate in skeletal development, growth, and pathology: the case of hereditary multiple exostoses". Developmental Dynamics. 242 (9): 1021–32. doi:10.1002/dvdy.24010. PMC 4007065. PMID 23821404.
  12. 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.
  13. Bakthisaran, Raman; Tangirala, Ramakrishna; Rao, Ch. Mohan (1 April 2015). "Small heat shock proteins: Role in cellular functions and pathology". Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics. 1854 (4): 291–319. doi:10.1016/j.bbapap.2014.12.019. ISSN 1570-9639. PMID 25556000.
  14. Simmons, Andrew D.; Musy, Maurice M.; Lopes, Carla S.; Hwang, Larn-Yuan; Yang, Ya-Ping; Lovett, Michael (1 November 1999). "A Direct Interaction Between EXT Proteins and Glycosyltransferases is Defective in Hereditary Multiple Exostoses". Human Molecular Genetics. 8 (12): 2155–2164. doi:10.1093/hmg/8.12.2155. ISSN 0964-6906. PMID 10545594.
  15. "EXT2 orthologs". NCBI. Retrieved 15 November 2019.
  16. Busse M, Feta A, Presto J, Wilén M, Grønning M, Kjellén L, Kusche-Gullberg M (November 2007). "Contribution of EXT1, EXT2, and EXTL3 to heparan sulfate chain elongation". The Journal of Biological Chemistry. 282 (45): 32802–10. doi:10.1074/jbc.M703560200. PMID 17761672.
  17. "Osteochondroma : Bone Tumor Cancer : Tumors of the bone". www.tumorsurgery.org. (3) Sarcoma Surgeon and Orthopedic Oncologist. Retrieved 15 November 2019.
  18. Chen XJ, Zhang H, Tan ZP, Hu W, Yang YF (November 2016). "Novel mutation of EXT2 identified in a large family with multiple osteochondromas". Molecular Medicine Reports. 14 (5): 4687–4691. doi:10.3892/mmr.2016.5814. PMC 5102042. PMID 27748933.
  19. Stickens D, Zak BM, Rougier N, Esko JD, Werb Z (November 2005). "Mice deficient in Ext2 lack heparan sulfate and develop exostoses". Development. 132 (22): 5055–68. doi:10.1242/dev.02088. PMC 2767329. PMID 16236767.

Further reading
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