A splice-site mutation leads to haploinsufficiency of EXT2 mRNA for a dominant trait in a large family with multiple osteochondromas

Journal of Orthopaedic Research

Volumn 28, Issue 11, 2010, Pages 1522-1530

  Yang, Liu ^a,b   Hui, Wing Sum ^a   Chan, Wilson C W ^a   Ng, Vivian C W ^a   Yam, Teresa H Y ^a   Leung, Helen C M ^a   Huang, Jian Dong ^a   Shum, Daisy K Y ^a   Jie, Qiang ^b   Cheung, Kenneth M C ^a   Cheah, Kathryn S E ^a   Luo, Zhoujing ^b   Chan, Danny ^a  

^a UNIVERSITY OF HONG KONG   (Hong Kong)

^b FOURTH MILITARY MEDICAL UNIVERSITY   (China)

Author keywords

Exostosis; EXT2; Glycosyltransferases; Multiple osteochondromas; Mutation

Indexed keywords

BETA GLUCURONIDASE; EXOSTOSIN 2; EXOSTOSIN-2; HEPARAN SULFATE; HEPARANASE; MESSENGER RNA; N ACETYLGLUCOSAMINYLTRANSFERASE;

ADOLESCENT; ADULT; AGED; ARTICLE; CARTILAGE CELL; CELL DIFFERENTIATION; CHILD; CYTOLOGY; FEMALE; GENETICS; HEREDITARY MULTIPLE EXOSTOSIS; HUMAN; MALE; METABOLISM; MIDDLE AGED; MUTATION; PRESCHOOL CHILD; RNA SPLICING;

ADOLESCENT; ADULT; AGED; CELL DIFFERENTIATION; CHILD; CHILD, PRESCHOOL; CHONDROCYTES; EXOSTOSES, MULTIPLE HEREDITARY; FEMALE; GLUCURONIDASE; HEPARITIN SULFATE; HUMANS; MALE; MIDDLE AGED; MUTATION; N-ACETYLGLUCOSAMINYLTRANSFERASES; RNA SPLICING; RNA, MESSENGER;

EID: 77957994385     PISSN: 07360266     EISSN: 1554527X     Source Type: Journal    
DOI: 10.1002/jor.21162     Document Type: Article

References (31)

1. Ahn J, Ludecke HJ, Lindow S, et al. 1995. Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1). Nat Genet 11:137-143.
2. Wu YQ, Heutink P, de Vries BB, et al. 1994. Assignment of a second locus for multiple exostoses to the pericentromeric region of chromosome 11. Hum Mol Genet 3:167-171.
3. Wuyts W, van Hui W, Wauters J, et al. 1996. Positional cloning of a gene involved in hereditary multiple exostoses. Hum Mol Genet 5:1547-1557.
4. Lonie L, Porter DE, Fraser M, et al. 2006. Determination of the mutation spectrum of the EXT1/EXT2 genes in British Caucasian patients with multiple osteochondromas, and exclusion of six candidate genes in EXT negative cases. Hum Mutat 27:1160.
5. Kojima H, Wada T, Seki H, et al. 2008. One third of Japanese patients with multiple osteochondromas may have mutations in genes other than EXT1 or EXT2. Genet Test 12:557-561.
6. Lind T, Tufaro F, McCormick C, et al. 1998. The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate. J Biol Chem 273:26265-26268.
7. McCormick C, Leduc Y, Martindale D, et al. 1998. The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate [see comments]. Nat Genet 19:158-161.
8. Busse M, Kusche-Gullberg M. 2003. In vitro polymerization of heparan sulfate backbone by the EXT proteins. J Biol Chem 278:41333-41337.
9. McCormick C, Duncan G, Goutsos KT, et al. 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. Proc Natl Acad Sci USA 97:668-673.
10. Koziel L, Kunath M, Kelly OG, et al. 2004. Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification. Dev Cell 6:801-813.
11. Kronenberg HM. 2003. Developmental regulation of the growth plate. Nature 423:332-336.
12. Hall CR, Cole WG, Haynes R, et al. 2002. Reevaluation of a genetic model for the development of exostosis in hereditary multiple exostosis. Am J Med Genet 112:1-5.
13. Xu L, Xia J, Jiang H, et al. 1999. Mutation analysis of hereditary multiple exostoses in the Chinese. Hum Genet 105:45-50.
14. Wuyts W, Van Hui W, De Boulle K, et al. 1998. Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses. Am J Hum Genet 62:346-354.
15. Pedrini E, De LA, Valente EM, et al. 2005. Novel EXT1 and EXT2 mutations identified by DHPLC in Italian patients with multiple osteochondromas. Hum Mutat 26:280.
16. Signori E, Massi E, Matera MG, et al. 2007. A combined analytical approach reveals novel EXT1/2 gene mutations in a large cohort of Italian multiple osteochondromas patients. Genes Chromosomes Cancer 46:470-477.
17. Seki H, Kubota T, Ikegawa S, et al. 2001. Mutation frequencies of EXT1 and EXT2 in 43 Japanese families with hereditary multiple exostoses. Am J Med Genet 99: 59-62.
18. Cheung PK, McCormick C, Crawford BE, et al. 2001. Etiological point mutations in the hereditary multiple exostoses gene EXT1: a functional analysis of heparan sulfate polymerase activity. Am J Hum Genet 69:55-66.
19. Korkko J, Annunen S, Pihlajamaa T, et al. 1998. Conformation sensitive gel electrophoresis for simple and accurate detection of mutations: comparison with denaturing gradient gel electrophoresis and nucleotide sequencing. Proc Natl Acad Sci USA 95:1681-1685.
20. Tsang KY, Chan D, Cheslett D, et al. 2007. Surviving endoplasmic reticulum stress is coupled to altered chondrocyte differentiation and function. PLoS Biol 5:e44.
21. Byers PH. 2002. Killing the messenger: new insights into nonsense-mediated mRNA decay. J Clin Invest 109:3-6.
22. Frischmeyer PA, Dietz HC. 1999. Nonsense-mediated mRNA decay in health and disease. Hum Mol Genet 8:1893-1900.
23. Bateman JF, Freddi S, Lamande SR, et al. 1999. Reliable and sensitive detection of premature termination mutations using a protein truncation test designed to overcome problems of nonsense-mediated mRNA instability. Hum Mutat 13:311-317.
24. Bernard MA, Hall CE, Hogue DA, et al. 2001. Diminished levels of the putative tumor suppressor proteins EXT1 and EXT2 in exostosis chondrocytes. Cell Motil Cytoskeleton 48:149-162.
25. Pannier S, Legeai-Mallet L. 2002. Hereditary multiple exostoses and enchondromatosis. Best Pract Res Clin Rheumatol 22:45-54.
26. Nadanaka S, Kitagawa H. 2008. Heparan sulphate biosynthesis and disease. J Biochem 144:7-14.
27. Kim BT, Kitagawa H, Tanaka J, et al. 2003. In vitro heparan sulfate polymerization: crucial roles of core protein moieties of primer substrates in addition to the EXT1-EXT2 interaction. J Biol Chem 278:41618-41623.
28. Francannet C, Cohen-Tanugi A, Le Merrer M, et al. 2001. Genotype-phenotype correlation in hereditary multiple exostoses. J Med Genet 38:430-434.
29. Tsuchiya T, Osanai T, Ogose A, et al. 2005. Methylation status of EXT1 and EXT2 promoters and two mutations of EXT2 in chondrosarcoma. Cancer Genet Cytogenet 158:148-155.
30. Stickens D, Zak BM, Rougier N, et al. 2005. Mice deficient in Ext2 lack heparan sulfate and develop exostoses. Development 132:5055-5068.
31. Lin X, Wei G, Shi Z, et al. 2000. Disruption of gastrulation and heparan sulfate biosynthesis in EXT1-deficient mice. Dev Biol 224:299-311.