RGD Reference Report - Identification of genetic loci affecting the severity of symptoms of Hirschsprung disease in rats carrying Ednrbsl mutations by quantitative trait locus analysis. - Rat Genome Database

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Identification of genetic loci affecting the severity of symptoms of Hirschsprung disease in rats carrying Ednrbsl mutations by quantitative trait locus analysis.

Authors: Huang, J  Dang, R  Torigoe, D  Lei, C  Lan, X  Chen, H  Sasaki, N  Wang, J  Agui, T 
Citation: Huang J, etal., PLoS One. 2015 Mar 19;10(3):e0122068. doi: 10.1371/journal.pone.0122068. eCollection 2015.
RGD ID: 10402048
Pubmed: PMID:25790447   (View Abstract at PubMed)
PMCID: PMC4366197   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0122068   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Hirschsprung's disease severityIDA 10402048 RGD 
Total Intestinal Aganglionosis severityIDA 10402048 RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
aganglionic megacolon severityIDA 10402048 RGD 
Objects Annotated

QTLs
Gdil2  (Gastrointestinal dilation QTL 2)

Strains
AR-Ednrbsl/Hkv  (Aganglionosis rat)
LEH/Hkv  (Aganglionosis rat)

Objects referenced in this article
Strain F344.AR-Ednrbsl/Hkv Aganglionosis rat Rattus norvegicus
QTL Gdil1 Gastrointestinal dilation QTL 1 Rattus norvegicus

Additional Information