A novel EXT2 frameshift mutation identified in a family with multiple osteochondromas

Chen,Zhonghua; Bi,Qing; Kong,Mingxiang; Cao,Li; Ruan,Weiwei

doi:10.3892/ol.2018.9248

A novel EXT2 frameshift mutation identified in a family with multiple osteochondromas

Authors:
- Zhonghua Chen
- Qing Bi
- Mingxiang Kong
- Li Cao
- Weiwei Ruan
View Affiliations

Affiliations: Graduate Department, Bengbu Medical College, Bengbu, Anhui 233003, P.R. China, Department of Orthopedics and Joint Surgery, Zhejiang Provincial People's Hospital, The People's Hospital of Hangzhou Medical College, Hangzhou, Zhejiang 310014, P.R. China, Department of Orthopedics, The Tongde Hospital of Zhejiang, Hangzhou, Zhejiang 310012, P.R. China
Published online on: August 1, 2018 https://doi.org/10.3892/ol.2018.9248
Pages: 5167-5171
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Multiple osteochondromas (MO) is an autosomal inherited disease that is characterized by benign bone tumors. However, the underlying mechanism of MO at a molecular level requires further investigation. The majority of mutations associated with MO occur in the exostosin glycosyltransferase genes (EXT)1 or EXT2. In the present study, the genetic causes of the disease were investigated. Polymerase chain reaction amplification, followed by DNA sequencing of the complete EXT1 and EXT2 coding regions, were conducted in a family with MO (n=5). A novel frameshift mutation in exon 3 of EXT2 (c.660delG) was detected. The production of a defective EXT2 protein, lacking 450 C‑terminal amino acid residues is predicted to be caused by the c.660delG mutation, located within the exostosin domain of EXT2. The missing residues contain the exostosin and glycosyltransferase family 64 domains, which are critical for the function of EXT2. The novel c.660delG frameshift mutation in the EXT2 gene extends the etiological understanding of MO and may provide an effective reference for genetic counseling and prenatal diagnosis in this family.

View Figures

View References

1	Wicklund CL, Pauli RM, Johnston D and Hecht JT: Natural history study of hereditary multiple exostoses. Am J Med Genet. 55:1–46. 1995. View Article : Google Scholar
2	Porter DE, Lonie L, Fraser M, Dobson-Stone C, Porter JR, Monaco AP and Simpson AH: Severity of disease and risk of malignant change in hereditary multiple exostoses. A genotype-phenotype study. J Bone Joint Surg Br. 86:1–1046. 2004.
3	Saglik Y, Altay M, Unal VS, Basarir K and Yildiz Y: Manifestations and management of osteochondromas: A retrospective analysis of 382 patients. Acta Orthop Belg. 72:1–755. 2006.PubMed/NCBI
4	Beltrami G, Ristori G, Scoccianti G, Tamburini A and Capanna R: Hereditary multiple exostoses: A review of clinical appearance and metabolic pattern. Clin Cases Miner Bone Metab. 13:110–118. 2016.PubMed/NCBI
5	Hennekam RC: Hereditary multiple exostoses. J Med Genet. 28:262–266. 1991. View Article : Google Scholar : PubMed/NCBI
6	Bovee JV: Multiple osteochondromas. Orphanet J Rare Dis. 3:32008. View Article : Google Scholar : PubMed/NCBI
7	Lonie L, Porter DE, Fraser M, Cole T, Wise C, Yates L, Wakeling E, Blair E, Morava E, Monaco AP and Ragoussis J: 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. 27:11602006. View Article : Google Scholar : PubMed/NCBI
8	Wuyts W, Radersma R, Storm K and Vits L: An optimized DHPLC protocol for molecular testing of the EXT1 and EXT2 genes in hereditary multiple osteochondromas. Clin Genet. 68:1–547. 2005. View Article : Google Scholar
9	Wuyts W and Van Hul W: Molecular basis of multiple exostoses: Mutations in the EXT1 and EXT2 genes. Hum Mutat. 15:220–227. 2000. View Article : Google Scholar : PubMed/NCBI
10	Esko JD and Selleck SB: Order out of chaos: Assembly of ligand binding sites in heparan sulfate. Annu Rev Biochem. 71:435–471. 2002. View Article : Google Scholar : PubMed/NCBI
11	McCormick C, Leduc Y, Martindale D, Mattison K, Esford LE, Dyer AP and Tufaro F: The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate. Nat Genet. 19:158–161. 1998. View Article : Google Scholar : PubMed/NCBI
12	Zak BM, Crawford BE and Esko JD: Hereditary multiple exostoses and heparan sulfate polymerization. Biochim Biophys Acta. 1573:346–355. 2002. View Article : Google Scholar : PubMed/NCBI
13	Jennes I, Pedrini E, Zuntini M, Mordenti M, Balkassmi S, Asteggiano CG, Casey B, Bakker B, Sangiorgi L and Wuyts W: Multiple osteochondromas: Mutation update and description of the multiple osteochondromas mutation database (MOdb). Hum Mutat. 30:1620–1627. 2009. View Article : Google Scholar : PubMed/NCBI
14	Wuyts W, Van Hul W, Wauters J, Nemtsova M, Reyniers E, Van Hul EV, De Boulle K, de Vries BB, Hendrickx J, Herrygers I, et al: Positional cloning of a gene involved in hereditary multiple exostoses. Hum Mol Genet. 5:1547–1557. 1996. View Article : Google Scholar : PubMed/NCBI
15	Lind T, Tufaro F, McCormick C, Lindahl U and Lidholt K: The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate. J Biol Chem. 273:26265–26268. 1998. View Article : Google Scholar : PubMed/NCBI
16	McCormick C, Duncan G, Goutsos KT and Tufaro F: 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. 2000. View Article : Google Scholar : PubMed/NCBI
17	Bernfield M, Götte M, Park PW, Reizes O, Fitzgerald ML, Lincecum J and Zako M: Functions of cell surface heparan sulfate proteoglycans. Annu Rev Biochem. 68:729–777. 1999. View Article : Google Scholar : PubMed/NCBI
18	Esko JD and Lindahl U: Molecular diversity of heparan sulfate. J Clin Invest. 108:169–173. 2001. View Article : Google Scholar : PubMed/NCBI
19	Tumova S, Woods A and Couchman JR: Heparan sulfate proteoglycans on the cell surface: Versatile coordinators of cellular functions. Int J Biochem Cell Biol. 32:269–288. 2000. View Article : Google Scholar : PubMed/NCBI
20	Williams KJ and Fuki IV: Cell-surface heparan sulfate proteoglycans: Dynamic molecules mediating ligand catabolism. Curr Opin Lipidol. 8:253–262. 1997. View Article : Google Scholar : PubMed/NCBI
21	Anower-E-Khuda MF, Matsumoto K, Habuchi H, Morita H, Yokochi T, Shimizu K and Kimata K: Glycosaminoglycans in the blood of hereditary multiple exostoses patients: Half reduction of heparan sulfate to chondroitin sulfate ratio and the possible diagnostic application. Glycobiology. 23:865–876. 2013. View Article : Google Scholar : PubMed/NCBI
22	Jones KB, Pacifici M and Hilton MJ: Multiple hereditary exostoses (MHE): Elucidating the pathogenesis of a rare skeletal disorder through interdisciplinary research. Connect Tissue Res. 55:80–88. 2014. View Article : Google Scholar : PubMed/NCBI
23	Xu L, Xia J, Jiang H, Zhou J, Li H, Wang D, Pan Q, Long Z, Fan C and Deng HX: Mutation analysis of hereditary multiple exostoses in the Chinese. Hum Genet. 105:45–50. 1999. View Article : Google Scholar : PubMed/NCBI