title: Identification of genetic loci affecting the severity of symptoms of Hirschsprung disease in rats carrying Ednrbsl mutations by quantitative trait locus analysis.
abstract: Hirschsprung's disease (HSCR) is a congenital disease in neonates characterized by the absence of the enteric ganglia in a variable length of the distal colon. This disease results from multiple genetic interactions that modulate the ability of enteric neural crest cells to populate developing gut. We previously reported that three rat strains with different backgrounds (susceptible AGH-Ednrbsl/sl, resistant F344-Ednrbsl/sl, and LEH-Ednrbsl/sl) but the same null mutation of Ednrb show varying severity degrees of aganglionosis. This finding suggests that strain-specific genetic factors affect the severity of HSCR. Consistent with this finding, a quantitative trait locus (QTL) for the severity of HSCR on chromosome (Chr) 2 was identified using an F2 intercross between AGH and F344 strains. In the present study, we performed QTL analysis using an F2 intercross between the susceptible AGH and resistant LEH strains to identify the modifier/resistant loci for HSCR in Ednrb-deficient rats. A significant locus affecting the severity of HSCR was also detected within the Chr 2 region. These findings strongly suggest that a modifier gene of aganglionosis exists on Chr 2. In addition, two potentially causative SNPs (or mutations) were detected upstream of a known HSCR susceptibility gene, Gdnf. These SNPs were possibly responsible for the varied length of gut affected by aganglionosis.
authors: College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China.
authors: Jieping
authors: J
authors: Huang
authors: College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China.
authors: Ruihua
authors: R
authors: Dang
authors: Laboratory of Laboratory Animal Science and Medicine, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Hokkaido, Japan.
authors: Daisuke
authors: D
authors: Torigoe
authors: College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China.
authors: Chuzhao
authors: C
authors: Lei
authors: College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China.
authors: Xianyong
authors: X
authors: Lan
authors: College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China.
authors: Hong
authors: H
authors: Chen
authors: Laboratory of Laboratory Animal Science and Medicine, School of Veterinary Medicine, Kitasato University, Aomori, Japan.
authors: Nobuya
authors: N
authors: Sasaki
authors: Laboratory of Laboratory Animal Science and Medicine, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Hokkaido, Japan.
authors: Jinxi
authors: J
authors: Wang
authors: Laboratory of Laboratory Animal Science and Medicine, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Hokkaido, Japan.
authors: Takashi
authors: T
authors: Agui
mesh_terms: D000818:Animals; D033481:Chromosomes, Mammalian / Q000235:genetics; D005260:Female; D041981:Gastrointestinal Tract / Q000473:pathology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006627:Hirschsprung Disease / Q000235:genetics* / Q000473:pathology; D006824:Hybridization, Genetic; D008297:Male; D009154:Mutation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics*; D051381:Rats; D044023:Receptor, Endothelin B / Q000235:genetics*
chemical_list: D044023:Receptor, Endothelin B