Genetic variation in the GDNF promoter affects its expression and modifies the severity of Hirschsprung's disease (HSCR) in rats carrying Ednrb(sl) mutations

Jieping Huang; Ruihua Dang; Daisuke Torigoe; Anqi Li; Chuzhao Lei; Nobuya Sasaki; Jinxi Wang; Takashi Agui

doi:10.1016/j.gene.2015.08.051

Genetic variation in the GDNF promoter affects its expression and modifies the severity of Hirschsprung's disease (HSCR) in rats carrying Ednrb(sl) mutations

Gene. 2016 Jan 1;575(1):144-8. doi: 10.1016/j.gene.2015.08.051. Epub 2015 Aug 28.

Authors

Jieping Huang¹, Ruihua Dang², Daisuke Torigoe³, Anqi Li⁴, Chuzhao Lei⁵, Nobuya Sasaki⁶, Jinxi Wang⁷, Takashi Agui⁷

Affiliations

¹ College of Life Sciences, Northwest A&F University, Yangling, Shaanxi, China; College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China.
² College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China. Electronic address: [email protected].
³ Laboratory of Laboratory Animal Science and Medicine, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Hokkaido, Japan; Division of Microbiology and Genetics, Center for Animal Resources and Development, Kumamoto, Japan.
⁴ College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China.
⁵ College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, China. Electronic address: [email protected].
⁶ Laboratory of Laboratory Animal Science and Medicine, School of Veterinary Medicine, Kitasato University, Aomori, Japan.
⁷ Laboratory of Laboratory Animal Science and Medicine, Department of Disease Control, Graduate School of Veterinary Medicine, Hokkaido University, Hokkaido, Japan.

PMID: 26318480
DOI: 10.1016/j.gene.2015.08.051

Abstract

Glial cell line-derived neurotrophic factor (GDNF) is necessary for the migration of neural crest stem cells in the gut. However, mutations in GDNF per se are deemed neither necessary nor sufficient to cause Hirschsprung's disease (HSCR). In a previous study, a modifier locus on chromosome 2 in rats carrying Ednrb(sl) mutations was identified, and several mutations in the putative regulatory region of the Gdnf gene in AGH-Ednrb(sl) rats were detected. Specifically, the mutation -232C>T has been shown to be strongly associated with the severity of HSCR. In the present study, the influence of genetic variations on the transcription of the Gdnf gene was tested using dual-luciferase assay. Results showed that the mutation -613C>T, located near the mutation -232C>T in AGH-Ednrb(sl) rats, decreased Gdnf transcription in an in vitro dual-luciferase expression assay. These data suggested an important role of -613C in Gdnf transcription. Expression levels of the Gdnf gene may modify the severity of HSCR in rats carrying Ednrb(sl) mutations.

Keywords: Dual-luciferase assay; Gdnf; Genetic variation; HSCR; Promoter.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line, Tumor
Chromosomes, Mammalian / genetics
Chromosomes, Mammalian / metabolism
Gene Expression Regulation*
Glial Cell Line-Derived Neurotrophic Factor* / biosynthesis
Glial Cell Line-Derived Neurotrophic Factor* / genetics
Hirschsprung Disease* / genetics
Hirschsprung Disease* / metabolism
Hirschsprung Disease* / pathology
Mutation*
Rats
Rats, Mutant Strains
Receptor, Endothelin B / genetics*
Receptor, Endothelin B / metabolism
Response Elements*

Substances

Glial Cell Line-Derived Neurotrophic Factor
Receptor, Endothelin B