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. 1998 Feb;62(2):346–354. doi: 10.1086/301726

Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses.

W Wuyts 1, W Van Hul 1, K De Boulle 1, J Hendrickx 1, E Bakker 1, F Vanhoenacker 1, F Mollica 1, H J Lüdecke 1, B S Sayli 1, U E Pazzaglia 1, G Mortier 1, B Hamel 1, E U Conrad 1, M Matsushita 1, W H Raskind 1, P J Willems 1
PMCID: PMC1376901  PMID: 9463333

Abstract

Hereditary multiple exostoses (EXT; MIM 133700) is an autosomal dominant bone disorder characterized by the presence of multiple benign cartilage-capped tumors (exostoses). Besides suffering complications caused by the pressure of these exostoses on the surrounding tissues, EXT patients are at an increased risk for malignant chondrosarcoma, which may develop from an exostosis. EXT is genetically heterogeneous, and three loci have been identified so far: EXT1, on chromosome 8q23-q24; EXT2, on 11p11-p12; and EXT3, on the short arm of chromosome 19. The EXT1 and EXT2 genes were cloned recently, and they were shown to be homologous. We have now analyzed the EXT1 and EXT2 genes, in 26 EXT families originating from nine countries, to identify the underlying disease-causing mutation. Of the 26 families, 10 families had an EXT1 mutation, and 10 had an EXT2 mutation. Twelve of these mutations have never been described before. In addition, we have reviewed all EXT1 and EXT2 mutations reported so far, to determine the nature, frequency, and distribution of mutations that cause EXT. From this analysis, we conclude that mutations in either the EXT1 or the EXT2 gene are responsible for the majority of EXT cases. Most of the mutations in EXT1 and EXT2 cause premature termination of the EXT proteins, whereas missense mutations are rare. The development is thus mainly due to loss of function of the EXT genes, consistent with the hypothesis that the EXT genes have a tumor- suppressor function.

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Selected References

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  1. Ahn J., Lüdecke H. J., Lindow S., Horton W. A., Lee B., Wagner M. J., Horsthemke B., Wells D. E. Cloning of the putative tumour suppressor gene for hereditary multiple exostoses (EXT1). Nat Genet. 1995 Oct;11(2):137–143. doi: 10.1038/ng1095-137. [DOI] [PubMed] [Google Scholar]
  2. Blanton S. H., Hogue D., Wagner M., Wells D., Young I. D., Hecht J. T. Hereditary multiple exostoses: confirmation of linkage to chromosomes 8 and 11. Am J Med Genet. 1996 Mar 15;62(2):150–159. doi: 10.1002/(SICI)1096-8628(19960315)62:2<150::AID-AJMG7>3.0.CO;2-#. [DOI] [PubMed] [Google Scholar]
  3. Cook A., Raskind W., Blanton S. H., Pauli R. M., Gregg R. G., Francomano C. A., Puffenberger E., Conrad E. U., Schmale G., Schellenberg G. Genetic heterogeneity in families with hereditary multiple exostoses. Am J Hum Genet. 1993 Jul;53(1):71–79. [PMC free article] [PubMed] [Google Scholar]
  4. Hecht J. T., Hogue D., Strong L. C., Hansen M. F., Blanton S. H., Wagner M. Hereditary multiple exostosis and chondrosarcoma: linkage to chromosome II and loss of heterozygosity for EXT-linked markers on chromosomes II and 8. Am J Hum Genet. 1995 May;56(5):1125–1131. [PMC free article] [PubMed] [Google Scholar]
  5. Hecht J. T., Hogue D., Wang Y., Blanton S. H., Wagner M., Strong L. C., Raskind W., Hansen M. F., Wells D. Hereditary multiple exostoses (EXT): mutational studies of familial EXT1 cases and EXT-associated malignancies. Am J Hum Genet. 1997 Jan;60(1):80–86. [PMC free article] [PubMed] [Google Scholar]
  6. Hennekam R. C. Hereditary multiple exostoses. J Med Genet. 1991 Apr;28(4):262–266. doi: 10.1136/jmg.28.4.262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Le Merrer M., Legeai-Mallet L., Jeannin P. M., Horsthemke B., Schinzel A., Plauchu H., Toutain A., Achard F., Munnich A., Maroteaux P. A gene for hereditary multiple exostoses maps to chromosome 19p. Hum Mol Genet. 1994 May;3(5):717–722. doi: 10.1093/hmg/3.5.717. [DOI] [PubMed] [Google Scholar]
  8. Legeai-Mallet L., Margaritte-Jeannin P., Lemdani M., Le Merrer M., Plauchu H., Maroteaux P., Munnich A., Clerget-Darpoux F. An extension of the admixture test for the study of genetic heterogeneity in hereditary multiple exostoses. Hum Genet. 1997 Mar;99(3):298–302. doi: 10.1007/s004390050361. [DOI] [PubMed] [Google Scholar]
  9. Lüdecke H. J., Ahn J., Lin X., Hill A., Wagner M. J., Schomburg L., Horsthemke B., Wells D. E. Genomic organization and promoter structure of the human EXT1 gene. Genomics. 1997 Mar 1;40(2):351–354. doi: 10.1006/geno.1996.4577. [DOI] [PubMed] [Google Scholar]
  10. Lüdecke H. J., Wagner M. J., Nardmann J., La Pillo B., Parrish J. E., Willems P. J., Haan E. A., Frydman M., Hamers G. J., Wells D. E. Molecular dissection of a contiguous gene syndrome: localization of the genes involved in the Langer-Giedion syndrome. Hum Mol Genet. 1995 Jan;4(1):31–36. doi: 10.1093/hmg/4.1.31. [DOI] [PubMed] [Google Scholar]
  11. Mollica F., Li Volti S., Guarneri B. New syndrome: exostoses, anetodermia, brachydactyly. Am J Med Genet. 1984 Dec;19(4):665–667. doi: 10.1002/ajmg.1320190406. [DOI] [PubMed] [Google Scholar]
  12. Philippe C., Porter D. E., Emerton M. E., Wells D. E., Simpson A. H., Monaco A. P. Mutation screening of the EXT1 and EXT2 genes in patients with hereditary multiple exostoses. Am J Hum Genet. 1997 Sep;61(3):520–528. doi: 10.1086/515505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Raskind W. H., Conrad E. U., Chansky H., Matsushita M. Loss of heterozygosity in chondrosarcomas for markers linked to hereditary multiple exostoses loci on chromosomes 8 and 11. Am J Hum Genet. 1995 May;56(5):1132–1139. [PMC free article] [PubMed] [Google Scholar]
  14. SOLOMON L. HEREDITARY MULTIPLE EXOSTOSIS. Am J Hum Genet. 1964 Sep;16:351–363. [PMC free article] [PubMed] [Google Scholar]
  15. Schmale G. A., Conrad E. U., 3rd, Raskind W. H. The natural history of hereditary multiple exostoses. J Bone Joint Surg Am. 1994 Jul;76(7):986–992. doi: 10.2106/00004623-199407000-00005. [DOI] [PubMed] [Google Scholar]
  16. Stickens D., Clines G., Burbee D., Ramos P., Thomas S., Hogue D., Hecht J. T., Lovett M., Evans G. A. The EXT2 multiple exostoses gene defines a family of putative tumour suppressor genes. Nat Genet. 1996 Sep;14(1):25–32. doi: 10.1038/ng0996-25. [DOI] [PubMed] [Google Scholar]
  17. Wells D. E., Hill A., Lin X., Ahn J., Brown N., Wagner M. J. Identification of novel mutations in the human EXT1 tumor suppressor gene. Hum Genet. 1997 May;99(5):612–615. doi: 10.1007/s004390050415. [DOI] [PubMed] [Google Scholar]
  18. 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. 1997 Jan;7(1):10–16. doi: 10.1101/gr.7.1.10. [DOI] [PubMed] [Google Scholar]
  19. Wu Y. Q., Heutink P., de Vries B. B., Sandkuijl L. A., van den Ouweland A. M., Niermeijer M. F., Galjaard H., Reyniers E., Willems P. J., Halley D. J. Assignment of a second locus for multiple exostoses to the pericentromeric region of chromosome 11. Hum Mol Genet. 1994 Jan;3(1):167–171. doi: 10.1093/hmg/3.1.167. [DOI] [PubMed] [Google Scholar]
  20. Wuyts W., Ramlakhan S., Van Hul W., Hecht J. T., van den Ouweland A. M., Raskind W. H., Hofstede F. C., Reyniers E., Wells D. E., de Vries B. Refinement of the multiple exostoses locus (EXT2) to a 3-cM interval on chromosome 11. Am J Hum Genet. 1995 Aug;57(2):382–387. [PMC free article] [PubMed] [Google Scholar]
  21. Wuyts W., Van Hul W., Hendrickx J., Speleman F., Wauters J., De Boulle K., Van Roy N., Van Agtmael T., Bossuyt P., Willems P. J. Identification and characterization of a novel member of the EXT gene family, EXTL2. Eur J Hum Genet. 1997 Nov-Dec;5(6):382–389. [PubMed] [Google Scholar]
  22. Wuyts W., Van Hul W., Wauters J., Nemtsova M., Reyniers E., Van Hul E. V., De Boulle K., de Vries B. B., Hendrickx J., Herrygers I. Positional cloning of a gene involved in hereditary multiple exostoses. Hum Mol Genet. 1996 Oct;5(10):1547–1557. doi: 10.1093/hmg/5.10.1547. [DOI] [PubMed] [Google Scholar]

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