Skip to main content
NCBI home page
Genetics logoLink to Genetics
. 1997 Feb;145(2):435–443. doi: 10.1093/genetics/145.2.435

Spectrum of Bmp5 Mutations from Germline Mutagenesis Experiments in Mice

P C Marker 1, K Seung 1, A E Bland 1, L B Russell 1, D M Kingsley 1
PMCID: PMC1207807  PMID: 9071596

Abstract

Over 40 years of mutagenesis experiments using the mouse specific-locus test have produced a large number of induced germline mutations at seven loci, among them the short ear locus. We have previously shown that the short ear locus encodes bone morphogenetic protein 5 (BMP5), a member of a large family of secreted signaling molecules that play key roles in axis formation, tissue differentiation, mesenchymal-epithelial interactions, and skeletal development. Here we examine 24 chemical- and radiation-induced mutations at the short ear locus. Sequence changes in the Bmp5 open reading frame confirm the importance of cysteine residues in the function of TGFβ superfamily members. The spectrum of N-ethyl-N-nitrosourea-induced mutations also provides new information about the basepair, sequence context, and strand specificity of germline mutations in mammals.

Full Text

The Full Text of this article is available as a PDF (2.0 MB).

Selected References

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

  1. Avraham K. B., Hasson T., Steel K. P., Kingsley D. M., Russell L. B., Mooseker M. S., Copeland N. G., Jenkins N. A. The mouse Snell's waltzer deafness gene encodes an unconventional myosin required for structural integrity of inner ear hair cells. Nat Genet. 1995 Dec;11(4):369–375. doi: 10.1038/ng1295-369. [DOI] [PubMed] [Google Scholar]
  2. Bhanot O. S., Grevatt P. C., Donahue J. M., Gabrielides C. N., Solomon J. J. In vitro DNA replication implicates O2-ethyldeoxythymidine in transversion mutagenesis by ethylating agents. Nucleic Acids Res. 1992 Feb 11;20(3):587–594. doi: 10.1093/nar/20.3.587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Burns P. A., Gordon A. J., Kunsmann K., Glickman B. W. Influence of neighboring base sequence on the distribution and repair of N-ethyl-N-nitrosourea-induced lesions in Escherichia coli. Cancer Res. 1988 Aug 15;48(16):4455–4458. [PubMed] [Google Scholar]
  4. Cordes S. P., Barsh G. S. The mouse segmentation gene kr encodes a novel basic domain-leucine zipper transcription factor. Cell. 1994 Dec 16;79(6):1025–1034. doi: 10.1016/0092-8674(94)90033-7. [DOI] [PubMed] [Google Scholar]
  5. Daopin S., Piez K. A., Ogawa Y., Davies D. R. Crystal structure of transforming growth factor-beta 2: an unusual fold for the superfamily. Science. 1992 Jul 17;257(5068):369–373. doi: 10.1126/science.1631557. [DOI] [PubMed] [Google Scholar]
  6. Ellison K. S., Dogliotti E., Connors T. D., Basu A. K., Essigmann J. M. Site-specific mutagenesis by O6-alkylguanines located in the chromosomes of mammalian cells: influence of the mammalian O6-alkylguanine-DNA alkyltransferase. Proc Natl Acad Sci U S A. 1989 Nov;86(22):8620–8624. doi: 10.1073/pnas.86.22.8620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Fossett N. G., Arbour-Reily P., Kilroy G., McDaniel M., Mahmoud J., Tucker A. B., Chang S. H., Lee W. R. Analysis of ENU-induced mutations at the Adh locus in Drosophila melanogaster. Mutat Res. 1990 Jul;231(1):73–85. doi: 10.1016/0027-5107(90)90178-7. [DOI] [PubMed] [Google Scholar]
  8. Gibson F., Walsh J., Mburu P., Varela A., Brown K. A., Antonio M., Beisel K. W., Steel K. P., Brown S. D. A type VII myosin encoded by the mouse deafness gene shaker-1. Nature. 1995 Mar 2;374(6517):62–64. doi: 10.1038/374062a0. [DOI] [PubMed] [Google Scholar]
  9. Green M. C. Mechanism of the pleiotropic effects of the short-ear mutant gene in the mouse. J Exp Zool. 1968 Feb;167(2):129–150. doi: 10.1002/jez.1401670202. [DOI] [PubMed] [Google Scholar]
  10. Griffith D. L., Keck P. C., Sampath T. K., Rueger D. C., Carlson W. D. Three-dimensional structure of recombinant human osteogenic protein 1: structural paradigm for the transforming growth factor beta superfamily. Proc Natl Acad Sci U S A. 1996 Jan 23;93(2):878–883. doi: 10.1073/pnas.93.2.878. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hill R. E., Favor J., Hogan B. L., Ton C. C., Saunders G. F., Hanson I. M., Prosser J., Jordan T., Hastie N. D., van Heyningen V. Mouse Small eye results from mutations in a paired-like homeobox-containing gene. Nature. 1992 Feb 20;355(6362):750–750. doi: 10.1038/355750a0. [DOI] [PubMed] [Google Scholar]
  12. Hustad C. M., Perry W. L., Siracusa L. D., Rasberry C., Cobb L., Cattanach B. M., Kovatch R., Copeland N. G., Jenkins N. A. Molecular genetic characterization of six recessive viable alleles of the mouse agouti locus. Genetics. 1995 May;140(1):255–265. doi: 10.1093/genetics/140.1.255. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Jansen J. G., Mohn G. R., Vrieling H., van Teijlingen C. M., Lohman P. H., van Zeeland A. A. Molecular analysis of hprt gene mutations in skin fibroblasts of rats exposed in vivo to N-methyl-N-nitrosourea or N-ethyl-N-nitrosourea. Cancer Res. 1994 May 1;54(9):2478–2485. [PubMed] [Google Scholar]
  14. Jones J., Peters J. The molecular characterization of an A:T to G:C transition in the Hbb-b1 gene of the murine homologue of hemoglobin Rainier. Biochem Genet. 1991 Dec;29(11-12):617–626. doi: 10.1007/BF02426875. [DOI] [PubMed] [Google Scholar]
  15. King J. A., Marker P. C., Seung K. J., Kingsley D. M. BMP5 and the molecular, skeletal, and soft-tissue alterations in short ear mice. Dev Biol. 1994 Nov;166(1):112–122. doi: 10.1006/dbio.1994.1300. [DOI] [PubMed] [Google Scholar]
  16. Kingsley D. M., Bland A. E., Grubber J. M., Marker P. C., Russell L. B., Copeland N. G., Jenkins N. A. The mouse short ear skeletal morphogenesis locus is associated with defects in a bone morphogenetic member of the TGF beta superfamily. Cell. 1992 Oct 30;71(3):399–410. doi: 10.1016/0092-8674(92)90510-j. [DOI] [PubMed] [Google Scholar]
  17. Kingsley D. M. The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms. Genes Dev. 1994 Jan;8(2):133–146. doi: 10.1101/gad.8.2.133. [DOI] [PubMed] [Google Scholar]
  18. Kingsley D. M. What do BMPs do in mammals? Clues from the mouse short-ear mutation. Trends Genet. 1994 Jan;10(1):16–21. doi: 10.1016/0168-9525(94)90014-0. [DOI] [PubMed] [Google Scholar]
  19. Klein J. C., Bleeker M. J., Lutgerink J. T., van Dijk W. J., Brugghe H. F., van den Elst H., van der Marel G. A., van Boom J. H., Westra J. G., Berns A. J. Use of shuttle vectors to study the molecular processing of defined carcinogen-induced DNA damage: mutagenicity of single O4-ethylthymine adducts in HeLa cells. Nucleic Acids Res. 1990 Jul 25;18(14):4131–4137. doi: 10.1093/nar/18.14.4131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kohler S. W., Provost G. S., Fieck A., Kretz P. L., Bullock W. O., Sorge J. A., Putman D. L., Short J. M. Spectra of spontaneous and mutagen-induced mutations in the lacI gene in transgenic mice. Proc Natl Acad Sci U S A. 1991 Sep 15;88(18):7958–7962. doi: 10.1073/pnas.88.18.7958. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kohrman D. C., Harris J. B., Meisler M. H. Mutation detection in the med and medJ alleles of the sodium channel Scn8a. Unusual splicing due to a minor class AT-AC intron. J Biol Chem. 1996 Jul 19;271(29):17576–17581. doi: 10.1074/jbc.271.29.17576. [DOI] [PubMed] [Google Scholar]
  22. Krawczak M., Reiss J., Cooper D. N. The mutational spectrum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum Genet. 1992 Sep-Oct;90(1-2):41–54. doi: 10.1007/BF00210743. [DOI] [PubMed] [Google Scholar]
  23. Lewis S. E., Johnson F. M., Skow L. C., Popp D., Barnett L. B., Popp R. A. A mutation in the beta-globin gene detected in the progeny of a female mouse treated with ethylnitrosourea. Proc Natl Acad Sci U S A. 1985 Sep;82(17):5829–5831. doi: 10.1073/pnas.82.17.5829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lindahl T., Sedgwick B., Sekiguchi M., Nakabeppu Y. Regulation and expression of the adaptive response to alkylating agents. Annu Rev Biochem. 1988;57:133–157. doi: 10.1146/annurev.bi.57.070188.001025. [DOI] [PubMed] [Google Scholar]
  25. Massagué J. The transforming growth factor-beta family. Annu Rev Cell Biol. 1990;6:597–641. doi: 10.1146/annurev.cb.06.110190.003121. [DOI] [PubMed] [Google Scholar]
  26. McPherron A. C., Lee S. J. GDF-3 and GDF-9: two new members of the transforming growth factor-beta superfamily containing a novel pattern of cysteines. J Biol Chem. 1993 Feb 15;268(5):3444–3449. [PubMed] [Google Scholar]
  27. Ozkaynak E., Schnegelsberg P. N., Jin D. F., Clifford G. M., Warren F. D., Drier E. A., Oppermann H. Osteogenic protein-2. A new member of the transforming growth factor-beta superfamily expressed early in embryogenesis. J Biol Chem. 1992 Dec 15;267(35):25220–25227. [PubMed] [Google Scholar]
  28. Pastink A., Vreeken C., Nivard M. J., Searles L. L., Vogel E. W. Sequence analysis of N-ethyl-N-nitrosourea-induced vermilion mutations in Drosophila melanogaster. Genetics. 1989 Sep;123(1):123–129. doi: 10.1093/genetics/123.1.123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Pearce S. R., Peters J., Ball S., Morgan M. J., Walker J. I., Faik P. Sequence characterization of ENU-induced mutants of glucose phosphate isomerase in mouse. Mamm Genome. 1995 Dec;6(12):858–861. doi: 10.1007/BF00292435. [DOI] [PubMed] [Google Scholar]
  30. Popp R. A., Bailiff E. G., Skow L. C., Johnson F. M., Lewis S. E. Analysis of a mouse alpha-globin gene mutation induced by ethylnitrosourea. Genetics. 1983 Sep;105(1):157–167. doi: 10.1093/genetics/105.1.157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. RUSSELL W. L. X-ray-induced mutations in mice. Cold Spring Harb Symp Quant Biol. 1951;16:327–336. doi: 10.1101/sqb.1951.016.01.024. [DOI] [PubMed] [Google Scholar]
  32. Richardson K. K., Richardson F. C., Crosby R. M., Swenberg J. A., Skopek T. R. DNA base changes and alkylation following in vivo exposure of Escherichia coli to N-methyl-N-nitrosourea or N-ethyl-N-nitrosourea. Proc Natl Acad Sci U S A. 1987 Jan;84(2):344–348. doi: 10.1073/pnas.84.2.344. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Russell L. B., Russell W. L. Spontaneous mutations recovered as mosaics in the mouse specific-locus test. Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13072–13077. doi: 10.1073/pnas.93.23.13072. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Russell L. B., Selby P. B., von Halle E., Sheridan W., Valcovic L. The mouse specific-locus test with agents other than radiations: interpretation of data and recommendations for future work. Mutat Res. 1981 May;86(3):329–354. doi: 10.1016/0165-1110(81)90010-5. [DOI] [PubMed] [Google Scholar]
  35. Sandulache R., Pretsch W., Chatterjee B., Gimbel W., Graw J., Favor J. Molecular analysis of four lactate dehydrogenase-A mutants in the mouse. Mamm Genome. 1994 Dec;5(12):777–780. doi: 10.1007/BF00292012. [DOI] [PubMed] [Google Scholar]
  36. Schlunegger M. P., Grütter M. G. An unusual feature revealed by the crystal structure at 2.2 A resolution of human transforming growth factor-beta 2. Nature. 1992 Jul 30;358(6385):430–434. doi: 10.1038/358430a0. [DOI] [PubMed] [Google Scholar]
  37. Shibuya T., Morimoto K. A review of the genotoxicity of 1-ethyl-1-nitrosourea. Mutat Res. 1993 Jul;297(1):3–38. doi: 10.1016/0165-1110(93)90005-8. [DOI] [PubMed] [Google Scholar]
  38. Skopek T. R., Walker V. E., Cochrane J. E., Craft T. R., Cariello N. F. Mutational spectrum at the Hprt locus in splenic T cells of B6C3F1 mice exposed to N-ethyl-N-nitrosourea. Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):7866–7870. doi: 10.1073/pnas.89.17.7866. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Smith W. C., McKendry R., Ribisi S., Jr, Harland R. M. A nodal-related gene defines a physical and functional domain within the Spemann organizer. Cell. 1995 Jul 14;82(1):37–46. doi: 10.1016/0092-8674(95)90050-0. [DOI] [PubMed] [Google Scholar]
  40. Su L. K., Kinzler K. W., Vogelstein B., Preisinger A. C., Moser A. R., Luongo C., Gould K. A., Dove W. F. Multiple intestinal neoplasia caused by a mutation in the murine homolog of the APC gene. Science. 1992 May 1;256(5057):668–670. doi: 10.1126/science.1350108. [DOI] [PubMed] [Google Scholar]
  41. Wozney J. M., Rosen V., Celeste A. J., Mitsock L. M., Whitters M. J., Kriz R. W., Hewick R. M., Wang E. A. Novel regulators of bone formation: molecular clones and activities. Science. 1988 Dec 16;242(4885):1528–1534. doi: 10.1126/science.3201241. [DOI] [PubMed] [Google Scholar]
  42. Zdarsky E., Favor J., Jackson I. J. The molecular basis of brown, an old mouse mutation, and of an induced revertant to wild type. Genetics. 1990 Oct;126(2):443–449. doi: 10.1093/genetics/126.2.443. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Zingg B. C., Pretsch W., Mohrenweiser H. W. Molecular analysis of four ENU induced triosephosphate isomerase null mutants in Mus musculus. Mutat Res. 1995 May;328(2):163–173. doi: 10.1016/0027-5107(95)00004-3. [DOI] [PubMed] [Google Scholar]

Articles from Genetics are provided here courtesy of Oxford University Press

RESOURCES