RGD Reference Report - QTL analysis identifies a modifier locus of aganglionosis in the rat model of Hirschsprung disease carrying Ednrb(sl) mutations. - Rat Genome Database

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QTL analysis identifies a modifier locus of aganglionosis in the rat model of Hirschsprung disease carrying Ednrb(sl) mutations.

Authors: Dang, R  Torigoe, D  Sasaki, N  Agui, T 
Citation: Dang R, etal., PLoS One. 2011;6(11):e27902. Epub 2011 Nov 22.
RGD ID: 6480215
Pubmed: (View Article at PubMed) PMID:22132166
DOI: Full-text: DOI:10.1371/journal.pone.0027902

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)xF344-Ednrb(sl)) F(1) 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.



Disease Annotations    

Phenotype Annotations    

Mammalian Phenotype
Objects Annotated

Genes (Rattus norvegicus)
Ednrb  (endothelin receptor type B)
Ednrbsl  (endothelin receptor type B, spotting lethal)

Genes (Mus musculus)
Ednrb  (endothelin receptor type B)

Genes (Homo sapiens)
EDNRB  (endothelin receptor type B)

QTLs
Gdil1  (Gastrointestinal dilation QTL 1)

Strains
AR-Ednrbsl/Hkv  (Aganglionosis rat)
F344.AR-Ednrbsl/Hkv  (Aganglionosis rat)
LE/Hkv.AR-Ednrbsl  (Aganglionosis rat)


Additional Information