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. 2001 Jul;38(7):430–434. doi: 10.1136/jmg.38.7.430

Genotype-phenotype correlation in hereditary multiple exostoses

C Francannet 1, A Cohen-Tanugi 1, M Le Merrer 1, A Munnich 1, J Bonaventure 1, L Legeai-Mallet 1
PMCID: PMC1757186  PMID: 11432960

Abstract

Hereditary multiple exostoses (HME) is a genetically heterogeneous autosomal dominant disorder characterised by the development of bony protuberances mainly located on the long bones. Three HME loci have been mapped to chromosomes 8q24 (EXT1), 11p11-13 (EXT2), and 19p (EXT3). The EXT1 and EXT2 genes encode glycosyltransferases involved in biosynthesis of heparan sulphate proteoglycans. Here we report on a clinical survey and mutation analysis of 42 HME French families and show that EXT1 and EXT2 accounted for more than 90% of HME cases in our series. Among them, 27/42 cases were accounted for by EXT1 (64%, four nonsense, 19 frameshift, three missense, and one splice site mutations) and 9/42 cases were accounted for by EXT2 (21%, four nonsense, two frameshift, two missense, and one splice site mutation). Overall, 31/36 mutations were expected to cause loss of protein function (86%). The most severe forms of the disease and malignant transformation of exostoses to chondrosarcomas were associated with EXT1 mutations. These findings provide the first genotype-phenotype correlation in HME and will, it is hoped, facilitate the clinical management of these patients.


Keywords: hereditary multiple exostoses; EXT1; EXT2; chondrosarcoma

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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. Bovée J. V., Cleton-Jansen A. M., Wuyts W., Caethoven G., Taminiau A. H., Bakker E., Van Hul W., Cornelisse C. J., Hogendoorn P. C. EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas. Am J Hum Genet. 1999 Sep;65(3):689–698. doi: 10.1086/302532. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Carroll K. L., Yandow S. M., Ward K., Carey J. C. Clinical correlation to genetic variations of hereditary multiple exostosis. J Pediatr Orthop. 1999 Nov-Dec;19(6):785–791. [PubMed] [Google Scholar]
  4. 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]
  5. 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]
  6. 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]
  7. Knudson A. G., Jr Mutation and cancer: statistical study of retinoblastoma. Proc Natl Acad Sci U S A. 1971 Apr;68(4):820–823. doi: 10.1073/pnas.68.4.820. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Kobayashi S., Morimoto K., Shimizu T., Takahashi M., Kurosawa H., Shirasawa T. Association of EXT1 and EXT2, hereditary multiple exostoses gene products, in Golgi apparatus. Biochem Biophys Res Commun. 2000 Feb 24;268(3):860–867. doi: 10.1006/bbrc.2000.2219. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. 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]
  11. Legeai-Mallet L., Munnich A., Maroteaux P., Le Merrer M. Incomplete penetrance and expressivity skewing in hereditary multiple exostoses. Clin Genet. 1997 Jul;52(1):12–16. doi: 10.1111/j.1399-0004.1997.tb02508.x. [DOI] [PubMed] [Google Scholar]
  12. Lind T., Tufaro F., McCormick C., Lindahl U., Lidholt K. The putative tumor suppressors EXT1 and EXT2 are glycosyltransferases required for the biosynthesis of heparan sulfate. J Biol Chem. 1998 Oct 9;273(41):26265–26268. doi: 10.1074/jbc.273.41.26265. [DOI] [PubMed] [Google Scholar]
  13. McCormick C., Duncan G., Goutsos K. T., 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 U S A. 2000 Jan 18;97(2):668–673. doi: 10.1073/pnas.97.2.668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. McCormick C., Leduc Y., Martindale D., Mattison K., Esford L. E., Dyer A. P., Tufaro F. The putative tumour suppressor EXT1 alters the expression of cell-surface heparan sulfate. Nat Genet. 1998 Jun;19(2):158–161. doi: 10.1038/514. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. 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]
  17. 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]
  18. 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]
  19. Van Hul W., Wuyts W., Hendrickx J., Speleman F., Wauters J., De Boulle K., Van Roy N., Bossuyt P., Willems P. J. Identification of a third EXT-like gene (EXTL3) belonging to the EXT gene family. Genomics. 1998 Jan 15;47(2):230–237. doi: 10.1006/geno.1997.5101. [DOI] [PubMed] [Google Scholar]
  20. Wei G., Bai X., Gabb M. M., Bame K. J., Koshy T. I., Spear P. G., Esko J. D. Location of the glucuronosyltransferase domain in the heparan sulfate copolymerase EXT1 by analysis of Chinese hamster ovary cell mutants. J Biol Chem. 2000 Sep 8;275(36):27733–27740. doi: 10.1074/jbc.M002990200. [DOI] [PubMed] [Google Scholar]
  21. Wicklund C. L., Pauli R. M., Johnston D., Hecht J. T. Natural history study of hereditary multiple exostoses. Am J Med Genet. 1995 Jan 2;55(1):43–46. doi: 10.1002/ajmg.1320550113. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. 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]
  24. Wuyts W., Van Hul W., De Boulle K., Hendrickx J., Bakker E., Vanhoenacker F., Mollica F., Lüdecke H. J., Sayli B. S., Pazzaglia U. E. Mutations in the EXT1 and EXT2 genes in hereditary multiple exostoses. Am J Hum Genet. 1998 Feb;62(2):346–354. doi: 10.1086/301726. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. 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]
  26. Wuyts W., Van Hul W. Molecular basis of multiple exostoses: mutations in the EXT1 and EXT2 genes. Hum Mutat. 2000;15(3):220–227. doi: 10.1002/(SICI)1098-1004(200003)15:3<220::AID-HUMU2>3.0.CO;2-K. [DOI] [PubMed] [Google Scholar]
  27. 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]
  28. 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. 1999 Jul-Aug;105(1-2):45–50. doi: 10.1007/s004399900058. [DOI] [PubMed] [Google Scholar]

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