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

Ruihua Dang,Daisuke Torigoe,Takashi Agui,Nobuya Sasaki,Shree Ram Singh

doi:10.1371/journal.pone.0027902

Ruihua Dang, Daisuke Torigoe + Show 3 more

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https://doi.org/10.1371/journal.pone.0027902

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Journal: PloS one	Publication Date: Nov 22, 2011
Citations: 47	License type: CC BY 4.0

Affiliation: Hokkaido University

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, Ednrbsl, was introgressed into the F344 strain, almost 60% of F344-Ednrbsl/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-Ednrbsl×F344-Ednrbsl) 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.

Highlights

Hirschsprung disease (HSCR) is a congenital malformation characterized by the absence of intramural ganglion cells along variable lengths of the distal gut
We found that when the sl mutation was introgressed into the F344 strain, the phenotype of aganglionosis was strongly modified [34]
We have confirmed that the variation in the expressivity of this disease between these two strains was caused from the extent of aganglionosis by whole-mount acetylcholinesterase (AChE) staining [34]

Summary

Introduction

Hirschsprung disease (HSCR) is a congenital malformation characterized by the absence of intramural ganglion cells along variable lengths of the distal gut. Several genes have been implicated in the development of HSCR, including the RET proto-oncogene [7,8,9], endothelin receptor B gene (EDNRB) [10,11,12,13,14,15,16,17], endothelin-3 gene (EDN3) [18,19], glial-cell-line-derived neurotrophic factor (GDNF) [20,21,22], SOX10 [23,24], NRTN [25], ECE1 [26], ZFHX1B [27], PHOX2B [28], KIAA1279 [29], TCF4 [26] Mutations in these genes explain only a minority of cases and the vast majority (80%) of HSCR heritability remains unknown [30]. The variable penetrance and expressivity of this disease are attributed to the complex genetic interactions between the known susceptibility loci and undiscovered susceptibility or modifier loci in the genetic background that modulates the ability of enteric neural crest cells to populate the developing gut [31]

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