Copyright © 2002 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 70, Issue 2, 435-447, 1 February 2002
doi:10.1086/338712
Gdnf Haploinsufficiency Causes Hirschsprung-Like Intestinal Obstruction and Early-Onset Lethality in Mice
Liya Shen1, **, José G. Pichel2, Thomas Mayeli1, Hannu Sariola3, Bai Lu1 and Heiner Westphal1, 
, 
1 National Institute of Child Health and Human Development, National Institutes of Health, Bethesda
2 Unidad de Investigación, Hospital de Mérida, Mérida, Spain
3 Institute of Biotechnology, University of Helsinki, Helsinki
Address for correspondence and reprints: Dr. Heiner Westphal, Laboratory of Molecular Genetics and Development, National Institute of Child Health and Human Development, National Institutes of Health, Building 6B, Room 413, Bethesda, MD 20814-2790** Present affiliation: Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute, National Institutes of Health, Bethesda.
Abstract
Hirschsprung disease (HSCR) is a common congenital disorder that results in intestinal obstruction and lethality, as a result of defective innervation of the gastrointestinal (GI) tract. Despite its congenital origin, the molecular etiology of HSCR remains elusive for >70% of patients. Although mutations in the c-RET receptor gene are frequently detected in patients with HSCR, mutations in the gene encoding its ligand (glial cell line–derived neurotrophic factor [GDNF]), are rarely found. In an effort to establish a possible link between human HSCR and mutations affecting the Gdnf locus, we studied a large population of mice heterozygous for a Gdnf null mutation. This Gdnf+/− mutant cohort recapitulates complex features characteristic of HSCR, including dominant inheritance, incomplete penetrance, and variable severity of symptoms. The lack of one functioning Gdnf allele causes a spectrum of defects in gastrointestinal motility and predisposes the mutant mice to HSCR-like phenotypes. As many as one in five Gdnf+/− mutant mice die shortly after birth. Using a transgenic marking strategy, we identified hypoganglionosis of the gastrointestinal tract as a developmental defect that renders the mutant mice susceptible to clinical symptoms of HSCR. Our findings offer a plausible way to link an array of seemingly disparate features characteristic of a complex disease to a much more narrowly defined genetic cause. These findings may have general implications for the genetic analysis of cause and effect in complex human diseases.
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