title: RET and NRG1 interplay in Hirschsprung disease.
abstract: Hirschsprung disease (HSCR, aganglionic megacolon) is a complex genetic disorder of the enteric nervous system (ENS) characterized by the absence of enteric neurons along a variable length of the intestine. While rare variants (RVs) in the coding sequence (CDS) of several genes involved in ENS development lead to disease, the association of common variants (CVs) with HSCR has only been reported for RET (the major HSCR gene) and NRG1. Importantly, RVs in the CDS of these two genes are also associated with the disorder. To assess independent and joint effects between the different types of RET and NRG1 variants identified in HSCR patients, we used 254 Chinese sporadic HSCR patients and 143 ethnically matched controls for whom the RET and/or NRG1 variants genotypes (rare and common) were available. Four genetic risk factors were defined and interaction effects were modeled using conditional logistic regression analyses and pair-wise Kendall correlations. Our analysis revealed a joint effect of RET CVs with RET RVs, NRG1 CVs or NRG1 RVs. To assess whether the genetic interaction translated into functional interaction, mouse neural crest cells (NCCs; enteric neuron precursors) isolated from embryonic guts were treated with NRG1 (ErbB2 ligand) or/and GDNF (Ret ligand) and monitored during the subsequent neural differentiation process. Nrg1 inhibited the Gdnf-induced neuronal differentiation and Gdnf negatively regulated Nrg1-signaling by down-regulating the expression of its receptor, ErbB2. This preliminary data suggest that the balance neurogenesis/gliogenesis is critical for ENS development.
authors: Department of Psychiatry, The University of Hong Kong, Hong Kong SAR, China. allenkuei@gmail.com
authors: Hongsheng
authors: H
authors: Gui
authors: Wai-Kiu
authors: WK
authors: Tang
authors: Man-Ting
authors: MT
authors: So
authors: Petroola
authors: P
authors: Proitsi
authors: Pak C
authors: PC
authors: Sham
authors: Paul K
authors: PK
authors: Tam
authors: Elly Sau-Wai
authors: ES
authors: Ngan
authors: Elly
authors: E
authors: Sau-Wai Ngan
authors: Stacey S
authors: SS
authors: Cherny
authors: Maria-Mercè
authors: MM
authors: Garcia-Barceló
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D002681:China; D005260:Female; D014644:Genetic Variation / Q000235:genetics*; D023281:Genomics; D005838:Genotype; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D060148:HapMap Project; D006627:Hirschsprung Disease / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007422:Intestines / Q000166:cytology / Q000294:innervation; D015810:Linkage Disequilibrium; D008297:Male; D051379:Mice; D009154:Mutation; D009432:Neural Crest / Q000166:cytology; D020890:Neuregulin-1 / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics* / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors; D019076:Transgenes
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D020890:Neuregulin-1; D051096:Proto-Oncogene Proteins c-ret; D018719:Erb-b2 Receptor Tyrosine Kinases; C495039:GDNF protein, human; C094131:NRG1 protein, human; C508053:ERBB2 protein, human; C099282:RET protein, human
references: BMC Med Genet. 2011 Oct 13;12:138
references: 21995290
references: Neuron. 2003 Dec 4;40(5):905-16
references: 14659090
references: Am J Hum Genet. 2008 Feb;82(2):516-23
references: 18252232
references: J Med Genet. 2009 Dec;46(12):862-4
references: 19556619
references: Hum Mol Genet. 2005 Jan 15;14(2):191-204
references: 15548547
references: Science. 2008 Nov 7;322(5903):881-8
references: 18988837
references: Nat Genet. 2002 Oct;32(2):237-44
references: 12355085
references: J Pediatr Surg. 2012 Feb;47(2):299-302
references: 22325379
references: Nat Genet. 2008 Jun;40(6):695-701
references: 18509313
references: Nat Rev Neurosci. 2007 Jun;8(6):466-79
references: 17514199
references: Hum Mol Genet. 2005 Dec 15;14(24):3837-45
references: 16269442
references: Hum Mutat. 2005 Feb;25(2):189-95
references: 15643606
references: Gut. 2007 May;56(5):736
references: 17440194
references: Biochim Biophys Acta. 2007 Apr;1773(4):536-45
references: 17324478
references: Am J Physiol. 1998 Aug;275(2):G183-6
references: 9688643
references: PLoS Genet. 2009 Jul;5(7):e1000540
references: 19584936
references: Hum Mol Genet. 2010 Apr 15;19(8):1461-7
references: 20089534
references: Nat Rev Genet. 2010 Jun;11(6):446-50
references: 20479774
references: Nat Genet. 2011 Oct 23;43(12):1232-6
references: 22019782
references: PLoS One. 2011;6(12):e28986
references: 22174939
references: Hum Genet. 2012 Jan;131(1):67-76
references: 21706185
references: Stat Med. 2008 Jan 15;27(1):36-46
references: 17634969
references: Biochim Biophys Acta. 2008 Mar;1783(3):467-78
references: 18006159
references: Proc Natl Acad Sci U S A. 2009 Feb 24;106(8):2694-9
references: 19196962
references: Adv Anat Embryol Cell Biol. 2007;190:1-65
references: 17432114
references: Exp Cell Res. 2003 Mar 10;284(1):14-30
references: 12648463
references: J Hum Genet. 2012 May;57(5):286-93
references: 22377709
references: Am J Hum Genet. 2010 Jul 9;87(1):60-74
references: 20598273
references: J Clin Invest. 2011 Sep;121(9):3467-78
references: 21841314
references: PLoS One. 2011 Jan 20;6(1):e16181
references: 21283760
references: Am J Hum Genet. 2007 Sep;81(3):559-75
references: 17701901
references: Hum Mol Genet. 1996 Mar;5(3):351-4
references: 8852659
references: Biostatistics. 2005 Jan;6(1):1-9
references: 15618523
references: Nature. 2005 Apr 14;434(7035):857-63
references: 15829955
references: Am J Hum Genet. 2011 Jul 15;89(1):82-93
references: 21737059
references: PLoS One. 2010 Jun 02;5(6):e10918
references: 20532249
references: Gastroenterology. 2011 Feb;140(2):572-582.e2
references: 20977903
references: J Med Genet. 2008 Jan;45(1):1-14
references: 17965226
references: Nature. 1994 Jan 27;367(6461):380-3
references: 8114940