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. 1997 Nov;61(5):1117–1122. doi: 10.1086/301601

Genetic linkage of Paget disease of the bone to chromosome 18q.

J D Cody 1, F R Singer 1, G D Roodman 1, B Otterund 1, T B Lewis 1, M Leppert 1, R J Leach 1
PMCID: PMC1716035  PMID: 9345096

Abstract

Paget disease is a common bone disease characterized by abnormal osteoclasts that are large, multinucleated, and overactive and that contain paramyxovirus-like nuclear inclusions. There is evidence for a major genetic component to Paget disease, with up to 40% of patients having affected first-degree relatives; however, the locus (loci) and gene(s) involved are unknown. Another bone disorder, familial expansile osteolysis (FEO), although extremely rare, also is characterized by similar osteoclast abnormalities but has an earlier age at onset and a more aggressive clinical progression. The causative gene for FEO has been localized to a region of human chromosome 18q. On the basis of the presence of similar clinical findings and of viral-like nuclear inclusions in osteoclasts, we hypothesized that FEO and Paget disease are allelic versions of the same locus. Therefore, a large kindred with a high incidence of Paget disease was examined to determine if Paget disease was linked to genetic markers in the same region of chromosome 18 as that for FEO. Our analysis yielded a two-point LOD score of 3.40, with the genetic marker D18S42, a marker tightly linked to the FEO locus. This demonstrates that the gene(s) responsible for FEO and that for Paget disease are either closely linked or the same locus.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barker D. J., Gardner M. J. Distribution of Paget's disease in England, Wales and Scotland and a possible relationship with vitamin D deficiency in childhood. Br J Prev Soc Med. 1974 Nov;28(4):226–232. doi: 10.1136/jech.28.4.226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bell G. I., Karam J. H., Rutter W. J. Polymorphic DNA region adjacent to the 5' end of the human insulin gene. Proc Natl Acad Sci U S A. 1981 Sep;78(9):5759–5763. doi: 10.1073/pnas.78.9.5759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Beneton M. N., Harris S., Kanis J. A. Paramyxovirus-like inclusions in two cases of pycnodysostosis. Bone. 1987;8(4):211–217. doi: 10.1016/8756-3282(87)90167-0. [DOI] [PubMed] [Google Scholar]
  4. Bianco P., Silvestrini G., Ballanti P., Bonucci E. Paramyxovirus-like nuclear inclusions identical to those of Paget's disease of bone detected in giant cells of primary oxalosis. Virchows Arch A Pathol Anat Histopathol. 1992;421(5):427–433. doi: 10.1007/BF01606916. [DOI] [PubMed] [Google Scholar]
  5. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 1-1986. A 67-year-old man with Paget's disease and progressive leg weakness. N Engl J Med. 1986 Jan 9;314(2):105–113. doi: 10.1056/NEJM198601093140208. [DOI] [PubMed] [Google Scholar]
  6. Cody J. D., Pierce J. F., Brkanac Z., Plaetke R., Ghidoni P. D., Kaye C. I., Leach R. J. Preferential loss of the paternal alleles in the 18q- syndrome. Am J Med Genet. 1997 Mar 31;69(3):280–286. doi: 10.1002/(sici)1096-8628(19970331)69:3<280::aid-ajmg12>3.0.co;2-n. [DOI] [PubMed] [Google Scholar]
  7. Dib C., Fauré S., Fizames C., Samson D., Drouot N., Vignal A., Millasseau P., Marc S., Hazan J., Seboun E. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature. 1996 Mar 14;380(6570):152–154. doi: 10.1038/380152a0. [DOI] [PubMed] [Google Scholar]
  8. Dickson G. R., Shirodria P. V., Kanis J. A., Beneton M. N., Carr K. E., Mollan R. A. Familial expansile osteolysis: a morphological, histomorphometric and serological study. Bone. 1991;12(5):331–338. doi: 10.1016/8756-3282(91)90019-f. [DOI] [PubMed] [Google Scholar]
  9. Gherardi G., Lo Cascio V., Bonucci E. Fine structure of nuclei and cytoplasm of osteoclasts in Paget's disease of bone. Histopathology. 1980 Jan;4(1):63–74. doi: 10.1111/j.1365-2559.1980.tb02898.x. [DOI] [PubMed] [Google Scholar]
  10. Hall J. M., Lee M. K., Newman B., Morrow J. E., Anderson L. A., Huey B., King M. C. Linkage of early-onset familial breast cancer to chromosome 17q21. Science. 1990 Dec 21;250(4988):1684–1689. doi: 10.1126/science.2270482. [DOI] [PubMed] [Google Scholar]
  11. Hamdy R. C. Clinical features and pharmacologic treatment of Paget's disease. Endocrinol Metab Clin North Am. 1995 Jun;24(2):421–436. [PubMed] [Google Scholar]
  12. Harvey L., Gray T., Beneton M. N., Douglas D. L., Kanis J. A., Russell R. G. Ultrastructural features of the osteoclasts from Paget's disease of bone in relation to a viral aetiology. J Clin Pathol. 1982 Jul;35(7):771–779. doi: 10.1136/jcp.35.7.771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hughes A. E., Shearman A. M., Weber J. L., Barr R. J., Wallace R. G., Osterberg P. H., Nevin N. C., Mollan R. A. Genetic linkage of familial expansile osteolysis to chromosome 18q. Hum Mol Genet. 1994 Feb;3(2):359–361. doi: 10.1093/hmg/3.2.359. [DOI] [PubMed] [Google Scholar]
  14. Jacobs T. P., Michelsen J., Polay J. S., D'Adamo A. C., Canfield R. E. Giant cell tumor in Paget's disease of bone: familial and geographic clustering. Cancer. 1979 Aug;44(2):742–747. doi: 10.1002/1097-0142(197908)44:2<742::aid-cncr2820440247>3.0.co;2-u. [DOI] [PubMed] [Google Scholar]
  15. Klein R. M., Norman A. Diagnostic procedures for Paget's disease. Radiologic, pathologic, and laboratory testing. Endocrinol Metab Clin North Am. 1995 Jun;24(2):437–450. [PubMed] [Google Scholar]
  16. Lathrop G. M., Lalouel J. M., Julier C., Ott J. Strategies for multilocus linkage analysis in humans. Proc Natl Acad Sci U S A. 1984 Jun;81(11):3443–3446. doi: 10.1073/pnas.81.11.3443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Le Beau M. M., Overhauser J., Straub R. E., Silverman G., Gilliam T. C., Ott J., O'Connell P., Francke U., Geurts van Kessel A. Report of the first international workshop on human chromosome 18 mapping. Cytogenet Cell Genet. 1993;63(2):78–96. [PubMed] [Google Scholar]
  18. Mills B. G., Singer F. R. Nuclear inclusions in Paget's disease of bone. Science. 1976 Oct 8;194(4261):201–202. doi: 10.1126/science.959849. [DOI] [PubMed] [Google Scholar]
  19. Mills B. G., Yabe H., Singer F. R. Osteoclasts in human osteopetrosis contain viral-nucleocapsid-like nuclear inclusions. J Bone Miner Res. 1988 Feb;3(1):101–106. doi: 10.1002/jbmr.5650030115. [DOI] [PubMed] [Google Scholar]
  20. Morales-Piga A. A., Rey-Rey J. S., Corres-González J., García-Sagredo J. M., López-Abente G. Frequency and characteristics of familial aggregation of Paget's disease of bone. J Bone Miner Res. 1995 Apr;10(4):663–670. doi: 10.1002/jbmr.5650100421. [DOI] [PubMed] [Google Scholar]
  21. Rebel A., Malkani K., Basle M. Anomalies nucléaires des ostéoclastes de la maladie osseuse de Paget. Nouv Presse Med. 1974 May 18;3(20):1299–1301. [PubMed] [Google Scholar]
  22. Rebel A., Malkani K., Baslé M., Bregeon C. Osteoclast ultrastructure in Paget's disease. Calcif Tissue Res. 1976 Apr 20;(2):187–199. doi: 10.1007/BF02546407. [DOI] [PubMed] [Google Scholar]
  23. Reddy S. V., Singer F. R., Roodman G. D. Bone marrow mononuclear cells from patients with Paget's disease contain measles virus nucleocapsid messenger ribonucleic acid that has mutations in a specific region of the sequence. J Clin Endocrinol Metab. 1995 Jul;80(7):2108–2111. doi: 10.1210/jcem.80.7.7608263. [DOI] [PubMed] [Google Scholar]
  24. Siris E. S. Epidemiological aspects of Paget's disease: family history and relationship to other medical conditions. Semin Arthritis Rheum. 1994 Feb;23(4):222–225. doi: 10.1016/0049-0172(94)90037-x. [DOI] [PubMed] [Google Scholar]
  25. Sofaer J. A., Holloway S. M., Emery A. E. A family study of Paget's disease of bone. J Epidemiol Community Health. 1983 Sep;37(3):226–231. doi: 10.1136/jech.37.3.226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Vacher-Lavenu M. C., Louvel A., Daudet-Monsac M., Le Charpentier Y., Abelanet R. Inclusions tubulo-filamenteuses intranucléaires dans les cellules multinuclées des tumeurs à cellules géantes des os. Etude ultrastructurale d'une série de 31 tumeurs. C R Seances Acad Sci III. 1981 Nov 23;293(11):639–644. [PubMed] [Google Scholar]
  27. Wallace R. G., Barr R. J., Osterberg P. H., Mollan R. A. Familial expansile osteolysis. Clin Orthop Relat Res. 1989 Nov;(248):265–277. [PubMed] [Google Scholar]
  28. Welsh R. A., Meyer A. T. Nuclear fragmentations and associated fibrils in giant cell tumor of bone. Lab Invest. 1970 Jan;22(1):63–72. [PubMed] [Google Scholar]

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