Defective EXT1 (in EXT1:EXT2) does not transfer GlcNAc to the heparan chain

Stable Identifier
R-HSA-3656261
Type
Reaction [transition]
Species
Homo sapiens
Compartment
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Exostosin 1 and 2 (EXT1 and 2) are dual-specific glycosyltransferases required to form heparan sulfate (HS) which is involved in regulating variousbody functions during development, homeostasis and pathology including blood clotting, angiogenesis and metastasis of cancer cells. They are able to transfer N-acetylglucosamine (GlcNAc) and glucuronate (GlcA) to HS during its synthesis. Defects in EXT1 can cause hereditary multiple exostoses 1 (MIM:133700), an autosomal dominant disorder characterised by multiple projections of bone capped by cartilage resulting in deformed legs, forearms and hands (Petersen 1989). Trichorhinophalangeal syndrome, type II (TRPS2 aka Langer-Giedion syndrome, LGS) is a disorder that combines the clinical features of trichorhinophalangeal syndrome type I (TRPS1, MIM:190350) and multiple exostoses type I, caused by mutations in the TRPS1 and EXT1 genes, respectively (Langer et al. 1984, Ludecke et al. 1995; not annotated here). Defects in EXT1 such as frameshift mutations S478Lfs*43 and p.K177Efs*9 may also be responsible for chondrosarcoma (CHDS; MIM:215300) (Hecht et al. 1997; not annotated here).

Mutations that cause multiple exostoses 1 include L490Rfs*9, G198Afs*54, R339L, G339D and R340C (Ahn et al. 1995, Hecht et al. 1997, McCormick et al. 1998, Cheung et al. 2001, Xu et al. 1999).

Literature References
PubMed ID Title Journal Year
7550340 Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1)

Ahn, J, Lüdecke, HJ, Lindow, S, Horton, WA, Lee, B, Wagner, MJ, Horsthemke, B, Wells, DE

Nat. Genet. 1995
9620772 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

Nat. Genet. 1998
7711731 Molecular dissection of a contiguous gene syndrome: localization of the genes involved in the Langer-Giedion syndrome

Lüdecke, HJ, Wagner, MJ, Nardmann, J, La Pillo, B, Parrish, JE, Willems, PJ, Haan, EA, Frydman, M, Hamers, GJ, Wells, DE

Hum. Mol. Genet. 1995
11391482 Etiological point mutations in the hereditary multiple exostoses gene EXT1: a functional analysis of heparan sulfate polymerase activity

Cheung, PK, McCormick, C, Crawford, BE, Esko, JD, Tufaro, F, Duncan, G

Am. J. Hum. Genet. 2001
6496574 The tricho-rhino-phalangeal syndrome with exostoses (or Langer-Giedion syndrome): four additional patients without mental retardation and review of the literature

Langer, LO, Krassikoff, N, Laxova, R, Scheer-Williams, M, Lutter, LD, Gorlin, RJ, Jennings, CG, Day, DW

Am. J. Med. Genet. 1984
10480354 Mutation analysis of hereditary multiple exostoses in the Chinese

Xu, L, Xia, J, Jiang, H, Zhou, J, Li, H, Wang, D, Pan, Q, Long, Z, Fan, C, Deng, HX

Hum. Genet. 1999
8981950 Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies

Hecht, JT, Hogue, D, Wang, Y, Blanton, SH, Wagner, M, Strong, LC, Raskind, W, Hansen, MF, Wells, D

Am. J. Hum. Genet. 1997
Participants
Participant Of
Catalyst Activity
Catalyst Activity
Title
glucuronosyl-N-acetylglucosaminyl-proteoglycan 4-alpha-N-acetylglucosaminyltransferase activity of EXT1 mutants:EXT2 [Golgi membrane]
Physical Entity
Activity
Normal reaction
Disease
Name Identifier Synonyms
hereditary multiple exostoses 206 Osteochondromatosis syndrome (disorder) [Ambiguous], Multiple exostosis syndromes, Multiple congenital exostosis
Authored
Reviewed
Created