Nature Genetics
14, 341 - 344 (1996)
doi:10.1038/ng1196-341
Germline mutations in glial cell line-derived neurotrophic factor (GDNF) and RET in a Hirschsprung disease patientMisha Angrist1, Stacey Bolk1, Marc Halushka1, Paul A. Lapchak2
& Aravinda Chakravarti1, 3, 4
1Department of Genetics, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106-4955, USA
2Department of Neurosciences, MC 5-1-C, Amgen, 1840 DeHaviland Drive, Thousand Oaks, California 91320-1789, USA
3Center for Human Genetics, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio 44106-4955, USA
4e-mail: axc39@po.cwru.edu 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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