title: Gdnf haploinsufficiency causes Hirschsprung-like intestinal obstruction and early-onset lethality in mice.
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.
authors.affiliation: National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814-2790, USA.
authors.forename: Liya
authors.initials: L
authors.lastname: Shen
authors.forename: José G
authors.initials: JG
authors.lastname: Pichel
authors.forename: Thomas
authors.initials: T
authors.lastname: Mayeli
authors.forename: Hannu
authors.initials: H
authors.lastname: Sariola
authors.forename: Bai
authors.initials: B
authors.lastname: Lu
authors.forename: Heiner
authors.initials: H
authors.lastname: Westphal
mesh_terms: D017668:Age of Onset; D000375:Aging; D000483:Alleles; D000818:Animals; D000831:Animals, Newborn; D004064:Digestive System / Q000196:embryology / Q000294:innervation / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D005769:Gastrointestinal Motility / Q000235:genetics; D017353:Gene Deletion; D018628:Gene Dosage; D005799:Genes, Dominant / Q000235:genetics; D005804:Genes, Lethal / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006579:Heterozygote; D006627:Hirschsprung Disease / Q000196:embryology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D007415:Intestinal Obstruction / Q000196:embryology / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics*; D019683:Penetrance; D012727:Sex Characteristics; D014886:Weaning
chemical_list: C495039:GDNF protein, human; C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins