Germline mutations of the RET ligand GDNF are not sufficient to cause Hirschsprung disease

Nat Genet. 1996 Nov;14(3):345-7. doi: 10.1038/ng1196-345.


Hirschsprung disease (HSCR, aganglionic megacolon) is a common congenital malformation leading to bowel obstruction, with an incidence of 1/5,000 live births. It is characterized by the absence of intrinsic ganglion cells in the myenteric and submucosal plexuses along variable lengths of the gastrointestinal tract. As enteric neurons are derived from the vagal neural crest, HSCR is regarded as a neurocristopathy. On the basis of a skewed sex-ratio (M/F = 4/1) and a risk to relatives much higher than the incidence in the general population, HSCR has long been regarded as a sex-modified multifactorial disorder. Accordingly, segregation analysis suggested an incompletely penetrant dominant inheritance in HSCR families with aganglionosis extending beyond the sigmoid colon. We and others have mapped a dominant gene for HSCR to chromosome 10q11.2 and have ascribed the disease to mutations in the RET proto-oncogene. However, the lack of genotype-phenotype correlation, the low penetrance and the sex-dependent effect of RET mutations supported the existence of one or more modifier gene(s) in familial HSCR. In addition, thus far, RET mutations only accounted for 50% and 15-20% of familial and sporadic HSCR patients, respectively. RET encodes a tyrosine kinase receptor whose ligand was unknown. Recently, the Glial cell line-derived neurotrophic factor (GDNF) has been identified to be a ligand for RET. Moreover, Gdnf-/- knockout mutant mice display congenital intestinal aganglionosis and renal agenesis, a phenotype very similar to the Ret-/- mouse. These data prompted us to hypothesize that mutations of the gene encoding GDNF could either cause or modulate the HSCR phenotype in some cases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Drosophila Proteins*
  • Female
  • Germ-Line Mutation*
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Hirschsprung Disease / genetics*
  • Humans
  • Male
  • Nerve Growth Factors*
  • Nerve Tissue Proteins / genetics*
  • Pedigree
  • Phenotype
  • Polymorphism, Single-Stranded Conformational
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases / genetics
  • Sequence Analysis, DNA


  • Drosophila Proteins
  • GDNF protein, human
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • MAS1 protein, human
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Proto-Oncogene Mas
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases
  • Ret protein, Drosophila