Two-hit model for sporadic congenital anomalies in mice with the disorganization mutation (original) (raw)

. 1993 May;52(5):866–874.

Abstract

Congenital anomalies have complex etiologies involving both genetic and nongenetic components. Many are sporadic, without obvious evidence for heritability. An important model for these anomalies is a mutation in laboratory mice that is called "disorganization" (Ds), which functions as a variable autosomal dominant and leads to a wide variety of congenital anomalies involving many developmental processes and systems. Variable expressivity, asymmetrical manifestations, and low penetrance suggest that somatic events determine the location and nature of these anomalies. A statistical analysis suggests that occurrence of anomalies in mice with the Ds mutation follows a Poisson distribution. These results suggest that congenital anomalies in mice with the Ds mutation occur independently of each other. We propose that Ds causes a heritable predisposition to congenital anomalies and that Ds and appropriate somatic events combine to compromise normal development. We also propose that some sporadic, nonheritable congenital anomalies involve somatic mutations at Ds-like loci. Ds may therefore serve not only as a model for developmental anomalies in cell fate and pattern formation but also for complex developmental traits showing variable expressivity, low penetrance, and sporadic occurrence in mice and humans.

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Selected References

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  1. Abel E. L., Sokol R. J. Fetal alcohol syndrome is now leading cause of mental retardation. Lancet. 1986 Nov 22;2(8517):1222–1222. doi: 10.1016/s0140-6736(86)92234-8. [DOI] [PubMed] [Google Scholar]
  2. Adams M. S., Niswander J. D. Developmental 'noise' and a congenital malformation. Genet Res. 1967 Dec;10(3):313–317. doi: 10.1017/s0016672300011071. [DOI] [PubMed] [Google Scholar]
  3. Collins F. S. Positional cloning: let's not call it reverse anymore. Nat Genet. 1992 Apr;1(1):3–6. doi: 10.1038/ng0492-3. [DOI] [PubMed] [Google Scholar]
  4. Donehower L. A., Harvey M., Slagle B. L., McArthur M. J., Montgomery C. A., Jr, Butel J. S., Bradley A. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992 Mar 19;356(6366):215–221. doi: 10.1038/356215a0. [DOI] [PubMed] [Google Scholar]
  5. Donnai D., Winter R. M. Disorganisation: a model for 'early amnion rupture'? J Med Genet. 1989 Jul;26(7):421–425. doi: 10.1136/jmg.26.7.421. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Duboule D. The vertebrate limb: a model system to study the Hox/HOM gene network during development and evolution. Bioessays. 1992 Jun;14(6):375–384. doi: 10.1002/bies.950140606. [DOI] [PubMed] [Google Scholar]
  7. Friend S. H., Bernards R., Rogelj S., Weinberg R. A., Rapaport J. M., Albert D. M., Dryja T. P. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature. 1986 Oct 16;323(6089):643–646. doi: 10.1038/323643a0. [DOI] [PubMed] [Google Scholar]
  8. Friend S. H., Horowitz J. M., Gerber M. R., Wang X. F., Bogenmann E., Li F. P., Weinberg R. A. Deletions of a DNA sequence in retinoblastomas and mesenchymal tumors: organization of the sequence and its encoded protein. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9059–9063. doi: 10.1073/pnas.84.24.9059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. HUMMEL K. P. Developmental anomalies in mice resulting from action of the gene, disorganization, a semi-dominant lethal. Pediatrics. 1959 Jan;23(1 Pt 2):212–221. [PubMed] [Google Scholar]
  10. HUMMEL K. P. The inheritance and expression of disorganization, an unusual mutation in the mouse. J Exp Zool. 1958 Apr;137(3):389–423. doi: 10.1002/jez.1401370303. [DOI] [PubMed] [Google Scholar]
  11. Hall J. G. Genomic imprinting: review and relevance to human diseases. Am J Hum Genet. 1990 May;46(5):857–873. [PMC free article] [PubMed] [Google Scholar]
  12. 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]
  13. Knudson A. G., Jr, Strong L. C. Mutation and cancer: a model for Wilms' tumor of the kidney. J Natl Cancer Inst. 1972 Feb;48(2):313–324. [PubMed] [Google Scholar]
  14. Kurnit D. M., Layton W. M., Matthysse S. Genetics, chance, and morphogenesis. Am J Hum Genet. 1987 Dec;41(6):979–995. [PMC free article] [PubMed] [Google Scholar]
  15. Lander E. S., Botstein D. Strategies for studying heterogeneous genetic traits in humans by using a linkage map of restriction fragment length polymorphisms. Proc Natl Acad Sci U S A. 1986 Oct;83(19):7353–7357. doi: 10.1073/pnas.83.19.7353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Li F. P., Fraumeni J. F., Jr Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med. 1969 Oct;71(4):747–752. doi: 10.7326/0003-4819-71-4-747. [DOI] [PubMed] [Google Scholar]
  17. Lin A. E. Two additional patients representing the possible human homologue for the mouse mutant disorganisation (Ds) J Med Genet. 1991 Sep;28(9):645–647. doi: 10.1136/jmg.28.9.645. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Lowry R. B., Yong S. L. Cleft lip and palate, sensorineural deafness, and sacral lipoma in two brothers: a possible example of the disorganisation mutant. J Med Genet. 1991 Feb;28(2):135–137. doi: 10.1136/jmg.28.2.135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Maini P. K., Solursh M. Cellular mechanisms of pattern formation in the developing limb. Int Rev Cytol. 1991;129:91–133. doi: 10.1016/s0074-7696(08)60510-0. [DOI] [PubMed] [Google Scholar]
  20. Malkin D., Li F. P., Strong L. C., Fraumeni J. F., Jr, Nelson C. E., Kim D. H., Kassel J., Gryka M. A., Bischoff F. Z., Tainsky M. A. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990 Nov 30;250(4985):1233–1238. doi: 10.1126/science.1978757. [DOI] [PubMed] [Google Scholar]
  21. Nadeau J. H., Cox R. Mouse chromosome 14. Mamm Genome. 1992;3(Spec No):S206–S219. doi: 10.1007/BF00648432. [DOI] [PubMed] [Google Scholar]
  22. Nadeau J. H., Davisson M. T., Doolittle D. P., Grant P., Hillyard A. L., Kosowsky M. R., Roderick T. H. Comparative map for mice and humans. Mamm Genome. 1992;3(9):480–536. doi: 10.1007/BF00778825. [DOI] [PubMed] [Google Scholar]
  23. Naguib K. K., Hamoud M. S., Khalil E. S., el-Khalifa M. Y. Human homologue for the mouse mutant disorganisation: does it exist? J Med Genet. 1991 Feb;28(2):138–139. doi: 10.1136/jmg.28.2.138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. PENROSE L. S. The genetical background of common diseases. Acta Genet Stat Med. 1953;4(2-3):257–265. doi: 10.1159/000150748. [DOI] [PubMed] [Google Scholar]
  25. Petzel M. A., Erickson R. P. Disorganisation: a possible cause of apparent conjoint twinning. J Med Genet. 1991 Oct;28(10):712–714. doi: 10.1136/jmg.28.10.712. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Selby P. B. A rapid method for preparing high quality alizarin stained skeletons of adult mice. Stain Technol. 1987 May;62(3):143–146. doi: 10.3109/10520298709107984. [DOI] [PubMed] [Google Scholar]
  27. Srivastava S., Zou Z. Q., Pirollo K., Blattner W., Chang E. H. Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature. 1990 Dec 20;348(6303):747–749. doi: 10.1038/348747a0. [DOI] [PubMed] [Google Scholar]
  28. Tabin C. J. Retinoids, homeoboxes, and growth factors: toward molecular models for limb development. Cell. 1991 Jul 26;66(2):199–217. doi: 10.1016/0092-8674(91)90612-3. [DOI] [PubMed] [Google Scholar]
  29. Tickle C. Retinoic acid and chick limb bud development. Dev Suppl. 1991;1:113–121. [PubMed] [Google Scholar]
  30. Winter R. M., Donnai D. A possible human homologue for the mouse mutant disorganisation. J Med Genet. 1989 Jul;26(7):417–420. doi: 10.1136/jmg.26.7.417. [DOI] [PMC free article] [PubMed] [Google Scholar]