Germline Mutations in Glial Cell Line-Derived Neurotrophic Factor (GDNF) and RET in a Hirschsprung Disease Patient

Nat Genet. 1996 Nov;14(3):341-4. doi: 10.1038/ng1196-341.

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 births. HSCR may be inherited as a single gene disorder with reduced penetrance or as a multigenic trait. HSCR mutations have been identified in the RET receptor tyrosine kinase, 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 -/-) mice. 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-/- animals. 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Chromosome Mapping
  • Chromosomes, Human, Pair 5
  • Drosophila Proteins*
  • Female
  • Genetic Markers
  • Germ-Line Mutation*
  • Glial Cell Line-Derived Neurotrophic Factor
  • Glial Cell Line-Derived Neurotrophic Factor Receptors
  • Heterozygote
  • Hirschsprung Disease / genetics*
  • Humans
  • Male
  • Mice
  • Models, Genetic
  • Molecular Sequence Data
  • Nerve Growth Factors*
  • Nerve Tissue Proteins / genetics*
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins / genetics*
  • Proto-Oncogene Proteins c-ret
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Sequence Analysis, DNA
  • Sequence Homology, Nucleic Acid

Substances

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

Associated data

  • GENBANK/L19062
  • GENBANK/L19063