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Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease

Abstract

HIRSCHSPRUNG'S disease is a genetic disorder of neural crest development affecting 1 in 5,000 births. It is characterized by the absence of intramural ganglion cells in the hindgut, which often results in partial to complete intestinal obstruction during the first years of life. An autosomal dominant gene causing this disease was recently mapped to chromosome 10q11.2 (refs 1, 2), using an interstitial deletion of this region isolated in a cell hybrid3,4. It was subsequently localized to a 250-kilobase interval which contains the RET proto-oncogene5. Using flanking intronic sequences as primers6 to amplify 12 of the 20 exons of RET from genomic DNA of 27 Hirschsprung's disease patients, we have now identified four mutations (one frameshift and three missense) that totally disrupt or partially change the structure of the tyrosine kinase domain of the RET protein (Ret). Mutations in the extracellular cysteine-rich domain of Ret have been identified previously7,8 in patients with multiple endocrine neoplasia type 2A, and a targeted mutation in the tyrosine kinase domain of the same gene produces intestinal aganglionosis and kidney agenesis in homozygous transgenic mice9. Our results support the hypothesis that RET, in addition to its potential role in tumorigenesis, plays a critical role in the embryogenesis of the mammalian enteric nervous system.

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References

  1. Lyonnet, S. et al. Nature Genet. 4, 346–350 (1993).

    Article  CAS  Google Scholar 

  2. Angrist, M. et al. Nature Genet. 4, 351–356 (1993).

    Article  CAS  Google Scholar 

  3. Martucciello, G. et al. Pediat. Surg. Int. 7, 308–310 (1992).

    Article  Google Scholar 

  4. Puliti, A. et al. Cytogenet. Cell Genet. 63, 102–106 (1993).

    Article  CAS  Google Scholar 

  5. Yin, L. et al. Hum. molec. Genet. 2, 1803–1808 (1993).

    Article  Google Scholar 

  6. Ceccherini, I. et al. Biochem. biophys. Res. Commun. 196, 1288–1295 (1993).

    Article  CAS  Google Scholar 

  7. Mulligan, L. M. et al. Nature 363, 458–460 (1993).

    Article  ADS  CAS  Google Scholar 

  8. Donis-Keller, H. et al. Hum. molec. Genet. 2, 851–856 (1993).

    Article  CAS  Google Scholar 

  9. Schuchkardt, A. D'Agati, V., Costantini, F. & Pachnis, V. Nature 367, 380–383 (1994).

    Article  ADS  Google Scholar 

  10. Takahashi, M., Ritz, J. & Cooper, G. M. Cell 42, 581–588 (1985).

    Article  CAS  Google Scholar 

  11. Fusco, A., Grieco, M., Santoro, M. & Berlingieri, M. T. Nature 328, 170–172 (1987).

    Article  ADS  CAS  Google Scholar 

  12. Ishizaka, Y., Ochiai, M., Tahira, T., Sugimura, T. & Nagao, M. Oncogene 4, 789–794 (1989).

    CAS  PubMed  Google Scholar 

  13. Kwok, J. B. J., Gardner, E., Warner, J. P., Ponder, B. A. J. & Mulligan, L. M. Oncogene 8, 2575–2582 (1993).

    CAS  PubMed  Google Scholar 

  14. Tahira, T., Ishizaka, Y., Itoh, F., Sugimura, T. & Nagao, M. Oncogene 5, 97–102 (1990).

    CAS  PubMed  Google Scholar 

  15. Iwamoto, T., Taniguchi, M., Asai, N., Ohkusu, K. & Nakashima, I. Oncogene 8, 1087–1091 (1993).

    CAS  Google Scholar 

  16. Bongarzone, I. et al. Molec. cell. Biol. 13, 358–366 (1993).

    Article  CAS  Google Scholar 

  17. Rodriguez, G. A. & Park, M. Molec. cell. Biol. 13, 6711–6722 (1993).

    Article  Google Scholar 

  18. Hanks, S. H., Quinn, A. M. & Hunter, T. Science 241, 42–52 (1988).

    Article  ADS  CAS  Google Scholar 

  19. Nocka, K. et al. EMBO J. 9, 1805–1813 (1990).

    Article  CAS  Google Scholar 

  20. Reith, A. D. et al. Genes Dev. 4, 390–400 (1990).

    Article  CAS  Google Scholar 

  21. Fleischman, R. A., Saltman, D. A., Stastny, V. & Sneimer, S. Proc. natn. Acad. Sci. U.S.A. 88, 1085–1089 (1991).

    Article  Google Scholar 

  22. Giebel, L. B. & Spritz, R. A. Proc. natn. Acad. Sci. U.S.A. 88, 8696–8699 (1991).

    Article  ADS  CAS  Google Scholar 

  23. Hofstra, R. W. et al. Nature 367, 375–376 (1994).

    Article  ADS  CAS  Google Scholar 

  24. Sanger, F., Nickken, S. & Coulson, A. R. Proc. natn. Acad. Sci. U.S.A. 74, 5463–5467 (1977).

    Article  ADS  CAS  Google Scholar 

  25. Orita, M., Suzuki, Y., Sekiya, T. & Hayashi, K. Genomics 5, 874–879 (1989).

    Article  CAS  Google Scholar 

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Romeo, G., Ronchetto, P., Luo, Y. et al. Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease. Nature 367, 377–378 (1994). https://doi.org/10.1038/367377a0

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