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Mutations of the RET proto-oncogene in Hirschsprung's disease

Nature volume 367, pages 378–380 (1994)Cite this article

Abstract

HIRSCHSPRUNG'S disease (HSCR)1 is a common condition (1 in 5,000 live births) resulting in intestinal obstruction in neonates2 and megacolon in infants and adults3. This disease has been ascribed to the absence of autonomic ganglion cells, which are derived from the neural crest, in the terminal hindgut4. Segregation analyses have suggested incompletely penetrant dominant inheritance in familial HSCR5. Recently, a gene for HSCR has been mapped to chromosome 10q11.2 (refs 6, 7). No recombination was observed between the disease locus and the locus for the RET proto-oncogene8, a protein tyrosine kinase gene expressed in the cells derived from the neural crest9,10. Here we report nonsense and missense mutations in the extracellular domain of RET protein (exons 2, 3, 5 and 6) in six unrelated probands and show that the mutant genotypes segregate with the disease in HSCR families. Mutations of RET have been previously reported in multiple endocrine neoplasia type 2A (MEN 2A)11,12. Thus, germ-line mutations of the RET gene may contribute either to developmental anomalies in HSCR or to inherited predisposition to cancer in MEN 2A.

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Author notes

  1. Arnold Munnich: To whom correspondence should be addressed.

Authors and Affiliations

  1. Service de Genetique Medicale, Clinique Chirurgicale Infantile et Unite de Recherches sur les Handicaps Genetiques de I'Enfant, INSERM U-393, Hopital Necker-Enfants Malades, 149, rue de Sevres, 75743, Paris, cedex 15, France

    Patrick Edery, Stanislas Lyonnet, Anna Pelet, Claire Nihoul-Fékété & Arnold Munnich

  2. CRC Human Cancer Genetics Research Group, Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QP, UK

    Lois M. Mulligan & Bruce A. J. Ponder

  3. Department of Biochemistry and Molecular Genetics, St Mary's Hospital Medical School, London, W2 1PG, UK

    Eleanore Dow

  4. Unite INSERM U-194, Hopital de la Pitie-Salpetriere, 75634, Paris, cedex 13, France

    Laurent Abel

  5. Mothercare Unit of Clinical Genetics, Institute of Child Health, Guilford Street, London, WC1N 1EH, UK

    Susan Holder

Authors
  1. Patrick Edery
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  4. Anna Pelet
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  8. Claire Nihoul-Fékété
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  9. Bruce A. J. Ponder
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  10. Arnold Munnich
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Edery, P., Lyonnet, S., Mulligan, L. et al. Mutations of the RET proto-oncogene in Hirschsprung's disease. Nature 367, 378–380 (1994). https://doi.org/10.1038/367378a0

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