Alternative titles; symbols
HGNC Approved Gene Symbol: EXTL1
Cytogenetic location: 1p36.11 Genomic coordinates (GRCh38): 1:26,021,775-26,036,464 (from NCBI)
The tumor suppressor genes EXT1 (608177) and EXT2 (608210) are associated with hereditary multiple exostoses and encode bifunctional glycosyltransferases essential for chain polymerization of heparan sulfate and its analog, heparin. Wise et al. (1997) identified another gene, which they called EXTL, that showed striking sequence similarity to both EXT1 and EXT2 at the nucleotide and amino acid sequence levels. Although the mRNA transcribed from this gene is similar in size to that of EXT1 and EXT2, its pattern of expression was quite different.
Of the 3 highly homologous EXT-like genes, EXTL1, EXTL2 (602411), and EXTL3 (605744), EXTL2 is an alpha-1,4-GlcNAc transferase I, the key enzyme that initiates the heparan sulfate/heparin synthesis. Kim et al. (2001) transiently expressed truncated forms of EXTL1 and EXTL3, lacking the putative NH2-terminal transmembrane and cytoplasmic domains, in COS-1 cells and found that the cells harbored alpha-GlcNAc transferase activity. Various results suggested that EXTL3 is most likely involved in both chain initiation and elongation, whereas EXTL1 is possibly involved only in the chain elongation of heparan sulfate, and perhaps of heparin as well. Thus, the acceptor specificities of the 5 family members are overlapping but distinct, except for EXT1 and EXT2, which have the same specificity. Thus, all of the 5 cloned human EXT gene family proteins harbor glycosyltransferase activities, which probably contribute to the synthesis of heparan sulfate and heparin.
Hall et al. (2002) proposed the EXTL genes as candidates for second mutations leading to the development of exostoses.
Exclusion Studies
Xu et al. (1999) examined the EXTL1 and EXTL2 genes for the presence of germline mutations in hereditary multiple exostosis patients and found none.
By radiation hybrid analysis and fluorescence in situ hybridization, Wise et al. (1997) mapped EXTL to 1p36.1 between D1S458 and D1S511, a region that frequently shows loss of heterozygosity in a variety of tumor types.
Hall, C. R., Cole, W. G., Haynes, R., Hecht, J. T. Reevaluation of a genetic model for the development of exostosis in hereditary multiple exostosis. Am. J. Med. Genet. 112: 1-5, 2002. [PubMed: 12239711] [Full Text: https://doi.org/10.1002/ajmg.10635]
Kim, B.-T., Kitagawa, H., Tamura, J., Saito, T., Kusche-Gullberg, M., Lindahl, U., Sugahara, K. Human tumor suppressor EXT gene family members EXTL1 and EXTL3 encode alpha-1,4-N-acetylglucosaminyltransferases that likely are involved in heparan sulfate/heparin biosynthesis. Proc. Nat. Acad. Sci. 98: 7176-7181, 2001. [PubMed: 11390981] [Full Text: https://doi.org/10.1073/pnas.131188498]
Wise, C. A., Clines, G. A., Massa, H., Trask, B. J., Lovett, M. Identification and localization of the gene for EXTL, a third member of the multiple exostoses gene family. Genome Res. 7: 10-16, 1997. [PubMed: 9037597] [Full Text: https://doi.org/10.1101/gr.7.1.10]
Xu, L., Xia, J., Jiang, H., Zhou, J., Li, H., Wang, D., Pan, Q., Long, Z., Fan, C., Deng, H.-X. Mutation analysis of hereditary multiple exostoses in the Chinese. Hum. Genet. 105: 45-50, 1999. [PubMed: 10480354] [Full Text: https://doi.org/10.1007/s004399900058]