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, 14 (6), e0217132

Null Mutation of the Endothelin Receptor Type B Gene Causes Embryonic Death in the GK Rat


Null Mutation of the Endothelin Receptor Type B Gene Causes Embryonic Death in the GK Rat

Jinxi Wang et al. PLoS One.


The Hirschsprung disease (HSCR) is an inherited disease that is controlled by multiple genes and has a complicated genetic mechanism. HSCR patients suffer from various extents of constipation due to dysplasia of the enteric nervous system (ENS), which can be so severe as to cause complete intestinal obstruction. Many genes have been identified as playing causative roles in ENS dysplasia and HSCR, among them the endothelin receptor type B gene (Ednrb) has been identified to play an important role. Mutation of Ednrb causes a series of symptoms that include deafness, pigmentary abnormalities, and aganglionosis. In our previous studies of three rat models carrying the same spotting lethal (sl) mutation on Ednrb, the haplotype of a region on chromosome (Chr) 2 was found to be responsible for the differing severities of the HSCR-like symptoms. To confirm that the haplotype of the responsible region on Chr 2 modifies the severity of aganglionosis caused by Ednrb mutation and to recreate a rat model with severe symptoms, we selected the GK inbred strain, whose haplotype in the responsible region on Chr 2 resembles that of the rat strain in which severe symptoms accompany the Ednrbsl mutation. An Ednrb mutation was introduced into the GK rat by crossing with F344-Ednrbsl and by genome editing. The null mutation of Ednrb was found to cause embryonic death in F2 progeny possessing the GK haplotype in the responsible region on Chr 2. The results of this study are unexpected, and they provide new clues and animal models that promise to contribute to studies on the genetic regulatory network in the development of ENS and on embryogenesis.

Conflict of interest statement

The authors have declared that no competing interests exist.


Fig 1
Fig 1. The haplotype and phenotype of F2(F344 × GK)-Ednrbsl/sl progeny.
(A) The 10-day-old offspring of F2(F344 × GK). Right, a pup carrying the Ednrb mutation showes very severe symptom. This pup has an obviously inflated intestine and a hypoplasia. Left, a healthy littermate. (B) The aganglionosis ratio and haplotype for 7 mutant F2 progeny. The aganglionosis severity was calculated as the aganglionosis ratio (agangliononic length divided by large intestine length). Four microsatellites located in the responsible region were selected for the genotyping of the F2(F344 × GK) generation, and the genotypes of microsatellite loci are listed in the table. F indicates the homozygous genotype of the F344 strain. H indicates the heterozygous genotype of GK and F344 rats. No mutant progeny that processed the homozygous genotype of the GK strain were found. (C) A schematic of the identified region on Chr 2. The candidate genes are marked in blue and the microsatellites are marked in red. The location of each marker and candidate gene is listed.

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Grant support

This work was supported in part by a grant from the Morinaga Foundation for Health and Nutrition (MM), of which grant number and URL to sponsor’s website were not available. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. There was no additional external funding received for this study.