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. 1997 Aug;61(2):363–369. doi: 10.1086/514844

Localization of a gene for autosomal dominant osteopetrosis (Albers-Schönberg disease) to chromosome 1p21.

W Van Hul 1, J Bollerslev 1, J Gram 1, E Van Hul 1, W Wuyts 1, O Benichou 1, F Vanhoenacker 1, P J Willems 1
PMCID: PMC1715917  PMID: 9311741

Abstract

Albers-Schönberg disease, the classical form of osteopetrosis, is an autosomal dominant condition with generalized increased skeletal density due to reduced bone resorption. Characteristic radiological findings are generalized osteosclerosis, with, most typically, end-plate sandwichlike thickening of the vertebrae (Rugger-Jersey spine) and the bone-within-bone (endobones) phenomenon. We studied an extended kindred with Albers-Schönberg disease and found linkage with several markers from chromosome 1p21. The Albers-Schönberg gene is located in a candidate region of approximately 8.5 cM flanked by markers D1S486 and D1S2792. A maximum LOD score (Z(max)) of 4.09 was obtained in multipoint analysis at loci D1S239/D1S248. Possible linkage of osteopetrosis to this chromosomal region was analyzed because the CSF-1 gene, which is mutated in the op/op mouse model for osteopetrosis, is located in 1p21. However, SSCP and mutation analysis in patients did not reveal any abnormality, which excludes the CSF-1 gene as the disease-causing gene. This was confirmed by refined physical mapping of the CSF-1 gene outside the candidate region for the Albers-Schönberg gene. The identification of the molecular defect underlying Albers-Schönberg disease will therefore be dependent on the isolation of other genes from an 8.5-cM candidate region on chromosome 1p21.

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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 P. E., Rabin M., Watson M., Breg W. R., Ruddle F. H., Verma I. M. Human c-fos oncogene mapped within chromosomal region 14q21----q31. Proc Natl Acad Sci U S A. 1984 Sep;81(18):5826–5830. doi: 10.1073/pnas.81.18.5826. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Beighton P., Horan F., Hamersma H. A review of the osteopetroses. Postgrad Med J. 1977 Aug;53(622):507–516. doi: 10.1136/pgmj.53.622.507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bollerslev J., Andersen P. E., Jr Radiological, biochemical and hereditary evidence of two types of autosomal dominant osteopetrosis. Bone. 1988;9(1):7–13. doi: 10.1016/8756-3282(88)90021-x. [DOI] [PubMed] [Google Scholar]
  4. Bollerslev J., Marks S. C., Jr, Pockwinse S., Kassem M., Brixen K., Steiniche T., Mosekilde L. Ultrastructural investigations of bone resorptive cells in two types of autosomal dominant osteopetrosis. Bone. 1993 Nov-Dec;14(6):865–869. doi: 10.1016/8756-3282(93)90316-3. [DOI] [PubMed] [Google Scholar]
  5. Bollerslev J. Osteopetrosis. A genetic and epidemiological study. Clin Genet. 1987 Feb;31(2):86–90. [PubMed] [Google Scholar]
  6. Cruts M., Backhovens H., Wang S. Y., Van Gassen G., Theuns J., De Jonghe C. D., Wehnert A., De Voecht J., De Winter G., Cras P. Molecular genetic analysis of familial early-onset Alzheimer's disease linked to chromosome 14q24.3. Hum Mol Genet. 1995 Dec;4(12):2363–2371. doi: 10.1093/hmg/4.12.2363. [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. Dracopoli N. C., Meisler M. H. Mapping the human amylase gene cluster on the proximal short arm of chromosome 1 using a highly informative (CA)n repeat. Genomics. 1990 May;7(1):97–102. doi: 10.1016/0888-7543(90)90523-w. [DOI] [PubMed] [Google Scholar]
  9. Gerritsen E. J., Vossen J. M., van Loo I. H., Hermans J., Helfrich M. H., Griscelli C., Fischer A. Autosomal recessive osteopetrosis: variability of findings at diagnosis and during the natural course. Pediatrics. 1994 Feb;93(2):247–253. [PubMed] [Google Scholar]
  10. Gisselbrecht S., Sola B., Fichelson S., Bordereaux D., Tambourin P., Mattei M. G., Simon D., Guenet J. L. The murine M-CSF gene is localized on chromosome 3. Blood. 1989 May 1;73(6):1742–1745. [PubMed] [Google Scholar]
  11. Gyapay G., Morissette J., Vignal A., Dib C., Fizames C., Millasseau P., Marc S., Bernardi G., Lathrop M., Weissenbach J. The 1993-94 Généthon human genetic linkage map. Nat Genet. 1994 Jun;7(2 Spec No):246–339. doi: 10.1038/ng0694supp-246. [DOI] [PubMed] [Google Scholar]
  12. Hayman A. R., Jones S. J., Boyde A., Foster D., Colledge W. H., Carlton M. B., Evans M. J., Cox T. M. Mice lacking tartrate-resistant acid phosphatase (Acp 5) have disrupted endochondral ossification and mild osteopetrosis. Development. 1996 Oct;122(10):3151–3162. doi: 10.1242/dev.122.10.3151. [DOI] [PubMed] [Google Scholar]
  13. Heinzmann C., Rajavashisth T., Rotter J., Lusis A. J. KpnI RFLP for the human CSF-1 gene. Nucleic Acids Res. 1989 Aug 11;17(15):6425–6425. doi: 10.1093/nar/17.15.6425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hodgkinson C. A., Moore K. J., Nakayama A., Steingrímsson E., Copeland N. G., Jenkins N. A., Arnheiter H. Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-helix-zipper protein. Cell. 1993 Jul 30;74(2):395–404. doi: 10.1016/0092-8674(93)90429-t. [DOI] [PubMed] [Google Scholar]
  15. Horton W. A., Schimke R. N., Iyama T. Osteopetrosis: further heterogeneity. J Pediatr. 1980 Oct;97(4):580–585. doi: 10.1016/s0022-3476(80)80012-6. [DOI] [PubMed] [Google Scholar]
  16. Hughes A. E., Newton V. E., Liu X. Z., Read A. P. A gene for Waardenburg syndrome type 2 maps close to the human homologue of the microphthalmia gene at chromosome 3p12-p14.1. Nat Genet. 1994 Aug;7(4):509–512. doi: 10.1038/ng0894-509. [DOI] [PubMed] [Google Scholar]
  17. Johnston C. C., Jr, Lavy N., Lord T., Vellios F., Merritt A. D., Deiss W. P., Jr Osteopetrosis. A clinical, genetic, metabolic, and morphologic study of the dominantly inherited, benign form. Medicine (Baltimore) 1968 Mar;47(2):149–167. [PubMed] [Google Scholar]
  18. Kahler S. G., Burns J. A., Aylsworth A. S. A mild autosomal recessive form of osteopetrosis. Am J Med Genet. 1984 Feb;17(2):451–464. doi: 10.1002/ajmg.1320170208. [DOI] [PubMed] [Google Scholar]
  19. Kawasaki E. S., Ladner M. B., Wang A. M., Van Arsdell J., Warren M. K., Coyne M. Y., Schweickart V. L., Lee M. T., Wilson K. J., Boosman A. Molecular cloning of a complementary DNA encoding human macrophage-specific colony-stimulating factor (CSF-1). Science. 1985 Oct 18;230(4723):291–296. doi: 10.1126/science.2996129. [DOI] [PubMed] [Google Scholar]
  20. Ladner M. B., Martin G. A., Noble J. A., Nikoloff D. M., Tal R., Kawasaki E. S., White T. J. Human CSF-1: gene structure and alternative splicing of mRNA precursors. EMBO J. 1987 Sep;6(9):2693–2698. doi: 10.1002/j.1460-2075.1987.tb02561.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Landegent J. E., Kluck P. M., Bolk M. W., Willemze R. The human macrophage colony-stimulating factor gene is localized at chromosome 1 band p21 and not at 5q33.1. Ann Hematol. 1992 Feb;64(2):110–111. doi: 10.1007/BF01715356. [DOI] [PubMed] [Google Scholar]
  22. Lathrop G. M., Lalouel J. M. Easy calculations of lod scores and genetic risks on small computers. Am J Hum Genet. 1984 Mar;36(2):460–465. [PMC free article] [PubMed] [Google Scholar]
  23. Loría-Cortés R., Quesada-Calvo E., Cordero-Chaverri C. Osteopetrosis in children: a report of 26 cases. J Pediatr. 1977 Jul;91(1):43–47. doi: 10.1016/s0022-3476(77)80441-1. [DOI] [PubMed] [Google Scholar]
  24. Marks S. C., Jr, Lane P. W. Osteopetrosis, a new recessive skeletal mutation on chromosome 12 of the mouse. J Hered. 1976 Jan-Feb;67(1):11–18. doi: 10.1093/oxfordjournals.jhered.a108657. [DOI] [PubMed] [Google Scholar]
  25. Marks S. C., Jr Pathogenesis of osteopetrosis in the ia rat: reduced bone resorption due to reduced osteoclast function. Am J Anat. 1973 Oct;138(2):165–189. doi: 10.1002/aja.1001380204. [DOI] [PubMed] [Google Scholar]
  26. Marks S. C., Jr, Seifert M. F., Lane P. W. Osteosclerosis, a recessive skeletal mutation on chromosome 19 in the mouse. J Hered. 1985 May-Jun;76(3):171–176. doi: 10.1093/oxfordjournals.jhered.a110059. [DOI] [PubMed] [Google Scholar]
  27. Morris C. M., Honeybone L. M., Hollings P. E., Fitzgerald P. H. Localization of the SRC oncogene to chromosome band 20q11.2 and loss of this gene with deletion (20q) in two leukemic patients. Blood. 1989 Oct;74(5):1768–1773. [PubMed] [Google Scholar]
  28. Moseley W. S., Seldin M. F. Definition of mouse chromosome 1 and 3 gene linkage groups that are conserved on human chromosome 1: evidence that a conserved linkage group spans the centromere of human chromosome 1. Genomics. 1989 Nov;5(4):899–905. doi: 10.1016/0888-7543(89)90132-8. [DOI] [PubMed] [Google Scholar]
  29. O'Connell J. R., Weeks D. E. The VITESSE algorithm for rapid exact multilocus linkage analysis via genotype set-recoding and fuzzy inheritance. Nat Genet. 1995 Dec;11(4):402–408. doi: 10.1038/ng1295-402. [DOI] [PubMed] [Google Scholar]
  30. Shapiro F. Osteopetrosis. Current clinical considerations. Clin Orthop Relat Res. 1993 Sep;(294):34–44. [PubMed] [Google Scholar]
  31. Sly W. S., Whyte M. P., Sundaram V., Tashian R. E., Hewett-Emmett D., Guibaud P., Vainsel M., Baluarte H. J., Gruskin A., Al-Mosawi M. Carbonic anhydrase II deficiency in 12 families with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. N Engl J Med. 1985 Jul 18;313(3):139–145. doi: 10.1056/NEJM198507183130302. [DOI] [PubMed] [Google Scholar]
  32. Soriano P., Montgomery C., Geske R., Bradley A. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell. 1991 Feb 22;64(4):693–702. doi: 10.1016/0092-8674(91)90499-o. [DOI] [PubMed] [Google Scholar]
  33. Tachibana M., Perez-Jurado L. A., Nakayama A., Hodgkinson C. A., Li X., Schneider M., Miki T., Fex J., Francke U., Arnheiter H. Cloning of MITF, the human homolog of the mouse microphthalmia gene and assignment to chromosome 3p14.1-p12.3. Hum Mol Genet. 1994 Apr;3(4):553–557. doi: 10.1093/hmg/3.4.553. [DOI] [PubMed] [Google Scholar]
  34. Tassabehji M., Newton V. E., Read A. P. Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene. Nat Genet. 1994 Nov;8(3):251–255. doi: 10.1038/ng1194-251. [DOI] [PubMed] [Google Scholar]
  35. Thomson R. G. Failure of bone resorption in a calf. Pathol Vet. 1966;3(3):234–246. doi: 10.1177/030098586600300307. [DOI] [PubMed] [Google Scholar]
  36. Wang Z. Q., Ovitt C., Grigoriadis A. E., Möhle-Steinlein U., Rüther U., Wagner E. F. Bone and haematopoietic defects in mice lacking c-fos. Nature. 1992 Dec 24;360(6406):741–745. doi: 10.1038/360741a0. [DOI] [PubMed] [Google Scholar]
  37. Whyte M. P., Murphy W. A., Fallon M. D., Sly W. S., Teitelbaum S. L., McAlister W. H., Avioli L. V. Osteopetrosis, renal tubular acidosis and basal ganglia calcification in three sisters. Am J Med. 1980 Jul;69(1):64–74. doi: 10.1016/0002-9343(80)90501-x. [DOI] [PubMed] [Google Scholar]
  38. Xiang K., Phillippe G., Seino M., Bonham K., Fugita D. J., Bell G. I. Dinucleotide repeat polymorphism in the human SRC gene on chromosome 20. Nucleic Acids Res. 1991 Dec 25;19(24):6967–6967. doi: 10.1093/nar/19.24.6967-a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Yoshida H., Hayashi S., Kunisada T., Ogawa M., Nishikawa S., Okamura H., Sudo T., Shultz L. D., Nishikawa S. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature. 1990 May 31;345(6274):442–444. doi: 10.1038/345442a0. [DOI] [PubMed] [Google Scholar]

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