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Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient

Nature Genetics volume 14, pages 341–344 (1996)Cite this article

Abstract

Hirschsprung disease (HSCR), or congenital aganglionic megacolon, is the most common cause of congenital bowel obstruction with an incidence of 1 in 5000 live births1. HSCR may be inherited as a single gene disorder with reduced penetrance or as a multigenic trait2. HSCR mutations have been identified in the RET receptor tyrosine kinase3–6, endothelin-B receptor (EDNRB) and its physiological ligand, endothelin 3 (EDN3). Although RET's ligand has remained elusive, it is expected to be an extracellular neurotrophic molecule expressed in the developing gut and kidney mesenchyme, based on the phenotypes of intestinal aganglionosis and renal agenesis observed in homozygous RET knockout (Ret−/−) mice7,8. The glial cell line-derived neurotrophic factor (GDNF) is such a molecule. Recently, mice carrying two null alleles for Gdnf were shown to exhibit phenotypes remarkably similar to Ret−/− animals9–11. We screened 106 unrelated HSCR patients for mutations in GDNF by direct sequencing. We identified one familial mutation in a HSCR patient with a known de novo RET mutation and malrotation of the gut. No haplotype sharing was evident in any of 36 HSCR kindreds typed for microsatellite markers surrounding GDNF on human chromosome 5p. Our data suggest that GDNF is a minor contributor to human HSCR susceptibility and that loss of its function in enteric neurogenesis may be compensated for by other neurotrophic factors or via other pathways. However, it may be that in rare instances, RET and GDNF mutations act in concert to produce an enteric phenotype.

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References

  1. Holschneider, A.M. (ed.) Hirschsprung's disease. (Thieme-Stratton, New York, 1982).

    Google Scholar 

  2. Badner, J.A., Sieber, W.K., Garver, K.L. & Chakravarti, A.A. . A genetic study of Hirschsprung disease. Am. J. Hum. Genet. 46, 565–580 (1990).

    Google Scholar 

  3. Angrist, M. et al. Mutation analysis of the RET receptor tyrosine kinase in Hirschsprung disease. Hum. Mol. Genet. 4, 821–830 (1995).

    Article  CAS  Google Scholar 

  4. Attié, T. et al. Diversity of RET proto-oncogene mutations in familial and sporadic Hirschsprung disease. Hum. Mol. Genet. 4, 1381–1386 (1995).

    Article  Google Scholar 

  5. Yin, L. et al. Heterogeneity and low detection rate of RET mutations in Hirschsprung disease. Eur. J. Hum. Genet. 2, 272–280 (1994).

    Article  CAS  Google Scholar 

  6. Mulligan, L.M. et al. Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene. Hum. Mol. Genet. 3, 2163–2167 (1994).

    Article  CAS  Google Scholar 

  7. Dressler, G.R. The pros and cons of c-ret. Curr. Biol. 4, 354–356 (1994).

    Article  CAS  Google Scholar 

  8. Schuchardt, A., D'Agati, V., Larsson-Blomberg, L., Costantini, F. & Pachnis, V. Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 367, 380–383 (1994).

    Article  CAS  Google Scholar 

  9. Moore, M.W. et al. Renal and neuronal abnormalities in mice lacking GDNF. Nature 382, 76–79 (1996).

    Article  CAS  Google Scholar 

  10. Pichel, J.G. et al. Defects in enteric innervation and kidney development in mice lacking GDNF. Nature 382, 73–76 (1996).

    Article  CAS  Google Scholar 

  11. Sánchez, M.P. et al. Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature 382, 70–73 (1996).

    Article  Google Scholar 

  12. Bodian, M. & Carter, C.O. A family study of Hirschsprung's disease. Ann. Hum. Genet. 28, 261–277 (1963).

    Article  Google Scholar 

  13. Angrist, M. et al. A gene for Hirschsprung disease (megacoton) in the pericentromeric region of chromosome 10. Nature Genet. 4, 351–356 (1993).

    Article  CAS  Google Scholar 

  14. Lyonnet, S. et al. A gene for Hirschsprung disease maps to the proximal long arm of chromosome 10. Nature Genet. 4, 346–350 (1993).

    Article  CAS  Google Scholar 

  15. Puffenberger, E.G. et al. Identity-by-descent and association mapping of a recessive gene for Hirschsprung disease on human chromosome 13q22. Hum. Mol. Genet. 3, 1217–1225 (1994).

    Article  CAS  Google Scholar 

  16. Edery, P. et al. Mutations of the RET proto-oncogene in Hirschsprung's disease. Nature 367, 378–380 (1994).

    Article  CAS  Google Scholar 

  17. Romeo, G. et al. Point mutations affecting the tyrosine kinase domain of the RET proto-oncogene in Hirschsprung's disease. Nature 367, 377–378 (1994).

    Article  CAS  Google Scholar 

  18. Puffenberger, E.G. et al. A missense mutation of the endothelin-B receptor gene in multigenic Hirschsprung disease. Cell 79, 1257–1266 (1994).

    Article  CAS  Google Scholar 

  19. Edery, P. et al. Mutation of the endothelin-3 gene in the Waardenburg-Hirschsprung disease (Shah-Waardenburg syndrome) Nature Genet. 12, 442–444 (1996).

    Article  CAS  Google Scholar 

  20. Hofstra, R.M.W. et al. A homozygous mutation in the endothelin-3 gene associated with a combined Waardenburg type 2 and Hirschsprung phenotype (Shah-Waardenburg syndrome). Nature Genet. 12, 445–447 (1996).

    Article  CAS  Google Scholar 

  21. Takahashi, M. et al. Cloning and expression of the ret proto-oncogene encoding a tyrosine kinase with two potential transmembrane domains. Oncogene 3, 571–578 (1988).

    CAS  Google Scholar 

  22. Pasini, B., Ceccherini, I. & Romeo, G. RET mutations in human disease. Trends Genet. 12, 138–144 (1996).

    Article  CAS  Google Scholar 

  23. Durbec, P.L., Larsson-Blomberg, L.B., Schuchardt, A., Costantini, F. & Pachnis, V. Common origin and developmental dependence on c-ret of subsets of enteric and sympathetic neuroblasts. Development 122, 349–358 (1996).

    CAS  Google Scholar 

  24. Lin, L.-F.H. et al. GDNF: a glial cell line–derived neurotrophic factor for midbrain dopaminergic neurons. Science 260, 1130–1132 (1993).

    Article  CAS  Google Scholar 

  25. Lapchak, P.A. Therapeutic potentials for glial cell line-derived neurotrophic factor (GDNF) based upon pharmacological activities in the CNS. Rev. Neurosci. (in the press).

  26. Buj-Bello, A. et al. GDNF is an age-specific survival factor for sensory and autonomic neurons. Neuron 15, 821–828 (1995).

    Article  CAS  Google Scholar 

  27. Henderson, C.E. et al. GDNF: a potent survival factor for motoneurons in peripheral nerve and muscle. Science 266, 1062–1064 (1994).

    Article  CAS  Google Scholar 

  28. Oppenheim, R.W. et al. Developing motor neurons rescued from programmed axotomy-induced cell death by GDNF. Nature 373, 344–346 (1995).

    Article  CAS  Google Scholar 

  29. Yan, Q., Matheson, C. & Lopez, O.T. In vivo neurotrophic effects of GDNF on neonatal and adult facial motor neurons. Nature 373, 341–344 (1995).

    Article  CAS  Google Scholar 

  30. Zurn, A.D. et al. Glial cell line-derived neurotrophic factor (GDNF), a new neurotrophic factor for motoneurones. Neuroreport 6, 113–118 (1994).

    Article  CAS  Google Scholar 

  31. Hellmich, H.L. et al. Embryonic expression of glial cell-line derived neurotrophic factor (GDNF) suggests multiple developmental roles in neural differentiation and epithelial-mesenchymal interactions. Mech. Dev. 54, 95–105 (1996).

    Article  CAS  Google Scholar 

  32. Kingsley, D.M., TGF-beta superfamily—new members, new receptors, and new genetic tests of function in different organisms. Genes Dev. 8, 133–146 (1994).

    Article  CAS  Google Scholar 

  33. Bermingham, N. et al. Human glial cell line-derived neurotrophic factor (GDNF) maps to chromosome 5. Hum. Genet. 96, 671–673 (1995).

    Article  CAS  Google Scholar 

  34. Schindelhauer, D. et al. The gene coding for glial cell line derived neurotrophic factor (GDNF) maps to chromosome 5p12–p13 Genomics 28, 605–607 (1995).

    Article  CAS  Google Scholar 

  35. Durbec, P. et al. GDNF signalling through the Ret receptor tyrosine kinase. Nature 381, 789–793 (1996).

    Article  CAS  Google Scholar 

  36. Jing, S. et al. GDNF-induced activation of the Ret protein tyrosine kinase is mediated by GDNFR-α, a novel receptor for GDNF. Cell 85, 1113–1124 (1996).

    Article  CAS  Google Scholar 

  37. Treanor, J.J.S. et al. Characterization of a multicomponent receptor for GDNF. Nature 382, 80–83 (1996).

    Article  CAS  Google Scholar 

  38. Trupp, M. et al. Functional receptor for GDNF encoded by the c-ret proto-oncogene. Nature 381, 785–789 (1996).

    Article  CAS  Google Scholar 

  39. Vyse, T.J. & Todd, J.A. Genetic analysis of autoimmune disease. Cell 85, 311–318 (1996).

    Article  CAS  Google Scholar 

  40. Dib, C. et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature 380, 152–154 (1996).

    Article  CAS  Google Scholar 

  41. Barbacid, M. Structural and functional properties of the TRK family of neurotrophin receptors. Ann. N. Y. Acad. Sci. 766, 442–458 (1995).

    Article  CAS  Google Scholar 

  42. Muenke, M. & Schell, U. Fibroblast-growth-factor receptor mutations in human skeletal disorders. Trends Genet. 11, 308–313 (1995).

    Article  CAS  Google Scholar 

  43. Ezoe, K. et al. Novel mutations and deletions of the KIT (steel factor receptor) gene in human piebaldism. Am. J. Hum. Genet. 56, 58–66 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Genetics, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio, 44106-4955, USA

    Misha Angrist, Stacey Bolk, Marc Halushka & Aravinda Chakravarti

  2. Department of Neurosciences, MC 5-1-C, Amgen, 1840 DeHaviland Drive, Thousand Oaks, California, 91320-1789, USA

    Paul A. Lapchak

  3. Center for Human Genetics, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio, 44106-4955, USA

    Aravinda Chakravarti

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  1. Misha Angrist
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Correspondence to Aravinda Chakravarti.

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Angrist, M., Bolk, S., Halushka, M. et al. Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patient. Nat Genet 14, 341–344 (1996). https://doi.org/10.1038/ng1196-341

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