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

Nature. 1994 Jan 27;367(6461):378-80. doi: 10.1038/367378a0.


Hirschsprung's disease (HSCR) is a common condition (1 in 5,000 live births) resulting in intestinal obstruction in neonates and megacolon in infants and adults. This disease has been ascribed to the absence of autonomic ganglion cells, which are derived from the neural crest, in the terminal hindgut. Segregation analyses have suggested incompletely penetrant dominant inheritance in familial HSCR. 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-oncogene, a protein tyrosine kinase gene expressed in the cells derived from the neural crest. 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). 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Chromosomes, Human, Pair 10
  • DNA Primers
  • Drosophila Proteins*
  • Female
  • Genetic Linkage
  • Germ-Line Mutation*
  • Hirschsprung Disease / enzymology
  • Hirschsprung Disease / genetics*
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation
  • Pedigree
  • Phenotype
  • Point Mutation
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins c-ret
  • Proto-Oncogenes*
  • Receptor Protein-Tyrosine Kinases / genetics*


  • DNA Primers
  • Drosophila Proteins
  • MAS1 protein, human
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Ret protein, Drosophila