Abstract Objective Hereditary multiple exostoses (HME) is an autosomal dominant monogenic disorder of paraplasia ossium. Mutations in EXT1 and EXT2 have been suggested to be responsible for over 70% of HME cases. This study aimed to analyze the clinical features and pathogenic mutations in a Chinese family with HME (6 patients in 24 members of 3 generations) and to review the relative literature regarding mutations in EXT1 and EXT2 in the Chinese population. Methods Clinical pedigree dada from a Chinese family of HME were collected and analysed. EXT gene mutations in this pedigree assessed by PCR and sequencing. Pubmed and Wanfang (a Chinese database) were searched for the literature related to gene mutations in Chinese HME patients. Results In the pedigree analyzed, the age of onset of HME was becoming younger, the disease was becoming more severe, and the number of osteochondromas was increasing, in successive generations. A splicing mutation IVS5+1G>A, first identified in Chinese population, was found in all diseased members of this pedigree. According the currently available literature, EXT1 and EXT2 mutations have been detected in 29% (26/90) and 43% (39/90) Chinese families with HME. Conclusions HME starts earlier and becomes more severe and extensive with each successive generation in members of the pedigree analyzed. A splicing mutation, IVS5+1G>A, of EXT1, first identified in Chinese population, may be responsible for HME in the studied pedigree. EXT1 and EXT2 mutation rates may be different between the Chinese and Western populations.
WANG Wei,QIU Zheng-Qing,SONG Hong-Mei. A splicing mutation of EXT1 in a Chinese pedigree with hereditary multiple exostoses[J]. CJCP, 2014, 16(2): 174-180.
WANG Wei,QIU Zheng-Qing,SONG Hong-Mei. A splicing mutation of EXT1 in a Chinese pedigree with hereditary multiple exostoses[J]. CJCP, 2014, 16(2): 174-180.
Wuyts W, Van Hul W. Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes[J]. Hum Mutat, 2000, 15(3): 220-227.
3.0.CO;2-K target="_blank">
Philippe C, Porter DE, Emerton ME, et al. Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses[J]. Am J Hum Genet, 1997, 61(3): 520-528.
[4]
Xiao CY, Wang J, Zhang SZ, et al. A novel deletion mutation of the EXT2 gene in a large Chinese pedigree with hereditary multipleexostosis[J]. Br J Cancer, 2001, 85(2): 176-181.
Zhu HY, Hu YL, Yang Y, et al. Mutation analysis and prenatal diagnosis of EXT1 gene mutations in Chinese patients withmultiple osteochondromas[J]. Chin Med J (Engl), 2011, 124(19): 3054-3057.
[7]
Kang Z, Peng F, Ling T. Mutation screening of EXT genes in Chinese patients with multiple osteochondromas[J]. Gene, 2012, 506(2): 298-300.
[8]
Wang X, Li L, Li J, et al. Pathogenic gene screening and mutation detection in a Chinese family with multiple osteochondroma[J]. Genet Test Mol Biomarkers, 2012, 16(7): 827-832.
[9]
Wen W, Zhang Y, Wang Y, et al. A novel mutation in the EXT1 gene identified in a Han Chinese kindred with hereditary multiple exostosis[J]. Genet Test Mol Biomarkers, 2010, 14(3): 371-376.
Li Y, Wang J, Li H, et al. A novel EXT1 gene mutation causing hereditary multiple exostoses in a Chinese pedigree[J]. Pathology, 2010, 42(1): 91-93.
[12]
Li Y, Wang D, Wang W, et al. Identification of four novel EXT1 and EXT2 mutations in five Chinese pedigrees with hereditary multiple exostoses[J]. Genet Test Mol Biomarkers, 2009, 13(6): 825-830.
[13]
Liu SG, Lu DG, Liu ZQ, et al. A novel mutation in EXT2 gene in a Chinese family with hereditary multiple exostoses[J]. Genet Test, 2008, 12(3): 331-332.
[14]
Liu SG, Li FF, Huang SZ, et al. A novel mutation in the EXT2 gene identified in two unrelated Chinese families with hereditary multiple exostoses[J]. Genet Test, 2007, 11(4): 445-449.
Wu Y, Xing X, Xu S, et al. Novel and recurrent mutations in the EXT1 and EXT2 genes in Chinese kindreds with multiple osteochondromas[J]. J Orthop Res, 2013, 31(9): 1492-1499.
[28]
Schmale GA, Conrad EU, Raskind WH. The natural history of hereditary multiple exostoses[J]. J Bone Joint Surg[Am], 1994, 76(7): 986-992.
[29]
Legeai M L, Munnich A, Maroteaux P, et al. Incomplete penetrance and expressivity skewing in hereditary multiple exostoses[J]. Clin Genet, 1997, 52(1): 12-16.
[30]
Wicklund LC, Pauli RM, Johnston D, et al. Natural history study of hereditary multiple exostoses[J]. Am J Med Genet, 1995, 55(1): 43-46.
Hecht JT, Hogue D, Wang Y, et al. Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXTassociated malignancies[J]. Am J Hum Genet, 1997, 60(1): 80-86.
Raskind WH, Conrad EU Ⅲ, Matsushita M, et al. Evaluation of locus heterogeneity and EXT1 mutations in 34 families with hereditary multiple exostoses[J]. Hum Mutat, 1998, 11(3): 231-239.
3.0.CO;2-K target="_blank">
[42]
Legeai M L, Margaritte JP, Lemdani M, et al. An extension of the admixture test for the study of genetic heterogeneity in hereditary multiple exostoses[J]. Hum Genet, 1997, 99(3): 298-302.
[43]
Hecht JT, Hogue D, Strong LC, et al. Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome 11 and loss of heterozygosity for EXT-linked markers on chromosomes 11 and 8[J]. Am J Hum Genet, 1995, 56(5): 1125-1131.
[44]
Raskind WH, Conrad EU, Chansky H, et al. Loss of heterozygosity in chondrosarcomas for markers linked to hereditary multiple exostoses loci on chromosomes 8 and 11[J]. Am J Hum Genet, 1995, 56(5): 1132-1139.
[45]
McCormick C, Leduc Y, Martindale D, et al. The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate[J]. Nature Genet, 1998, 19(2): 158-161.
[46]
McCormick C, Duncan G, Goutsos KT, et al. The putative tumor suppressors EXT1 and EXT2 form a stable complex that accumulates in the Golgi apparatus and catalyzes the synthesis of heparan sulfate[J]. Proc Nat Acad Sci, 2000, 97(2): 668-673.
