QTL Analysis Identifies a Modifier Locus of Aganglionosis in the Rat Model of Hirschsprung Disease Carrying Ednrbsl Mutations

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. In this study, we found that the null mutation of the Ednrb gene, thought indispensable for enteric neuron development, is insufficient to result in HSCR disease when bred onto a different genetic background in rats carrying Ednrb^sl mutations. 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 × F344-Ednrb^sl) F₁with 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.

Key words: Hirschsprung disease, Ednrb gene, genetic background, neural crest cell, QTL

Corresponding author:

Dr. Ruihua Dang, College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi 712100, China.

E-mail:  drh211@hotmail.com