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QTL Analysis Identifies a Modifier Locus of Aganglionosis in the Rat Model of Hirschsprung Disease Carrying Ednrb^[sl] Mutations

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Title: QTL Analysis Identifies a Modifier Locus of Aganglionosis in the Rat Model of Hirschsprung Disease Carrying Ednrb^[sl] Mutations
Authors: Dang, Ruihua Browse this author
Torigoe, Daisuke Browse this author
Sasaki, Nobuya Browse this author →KAKEN DB
Agui, Takashi Browse this author →KAKEN DB
Issue Date: 22-Nov-2011
Publisher: Public Library of Science
Journal Title: PLoS One
Volume: 6
Issue: 11
Start Page: e27902
Publisher DOI: 10.1371/journal.pone.0027902
Abstract: Hirschsprung disease (HSCR) exhibits complex genetics with incomplete penetrance and variable severity thought to result as a consequence of multiple gene interactions that modulate the ability of enteric neural crest cells to populate the developing gut. As reported previously, when the same null mutation of the Ednrb gene, Ednrb^[sl], was introgressed into the F344 strain, almost 60% of F344-Ednrb^[sl/sl] pups did not show any symptoms of aganglionosis, appearing healthy and normally fertile. These findings strongly suggested that the severity of HSCR was affected by strain-specific genetic factor (s). In this study, the genetic basis of such large strain differences in the severity of aganglionosis in the rat model was studied by whole-genome scanning for quantitative trait loci (QTLs) using an intercross of (AGH-Ednrb^[sl] x F344-Ednrb^[sl]) F1 with the varying severity of aganglionosis. Genome linkage analysis identified one significant QTL on chromosome 2 for the severity of aganglionosis. Our QTL analyses using rat models of HSCR revealed that multiple genetic factors regulated the severity of aganglionosis. Moreover, a known HSCR susceptibility gene, Gdnf, was found in QTL that suggested a novel non-coding sequence mutation in GDNF that modifies the penetrance and severity of the aganglionosis phenotype in EDNRB-deficient rats. A further identification and analysis of responsible genes located on the identified QTL could lead to the richer understanding of the genetic basis of HSCR development.
Rights: http://creativecommons.org/licenses/by/3.0/
Type: article
URI: http://hdl.handle.net/2115/47974
Appears in Collections:獣医学院・獣医学研究院 (Graduate School of Veterinary Medicine / Faculty of Veterinary Medicine) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 安居院 高志

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