title: Mutations in the NRG1 gene are associated with Hirschsprung disease.
abstract: Hirschsprung disease (HSCR, congenital colon aganglionosis) is a relatively common complex genetic condition caused by abnormal development of the enteric nervous system (ENS). Through a recent genome-wide association study conducted on Chinese HSCR patients, we identified a new HSCR contributing locus, neuregulin 1 (NRG1; 8p12), a gene known to be involved in the development of the ENS. As genes in which disease-associated common variants are found are to be considered as candidates for the search of deleterious rare variants (RVs) in the coding sequences, we sequenced the NRG1 exons of 358 sporadic HSCR patients and 333 controls. We identified a total of 13 different heterozygous RVs including 8 non-synonymous (A28G, E134K, V266L, H347Y, P356L, V486M, A511T, P608A) and 3 synonymous amino acid substitutions (P24P, T169T, L483L), a frameshift (E239fsX10), and a c.503-4insT insertion. Functional analysis of the most conserved non-synonymous substitutions, H347Y and P356L, showed uneven intracellular distribution and aberrant expression of the mutant proteins. Except for T169T and V486M, all variants were exclusive to HSCR patients. Overall, there was a statistically significant over-representation of NRG1 RVs in HSCR patients (p = 0.008). We show here that not only common, but also rare variants of the NRG1 gene contribute to HSCR. This strengthens the role of NRG1.
authors.affiliation: Department of Surgery, The University of Hong Kong, Hong Kong, China.
authors.forename: Clara Sze-Man
authors.initials: CS
authors.lastname: Tang
authors.forename: Elly Sau-Wai
authors.initials: ES
authors.lastname: Ngan
authors.forename: Wai-Kiu
authors.initials: WK
authors.lastname: Tang
authors.forename: Man-Ting
authors.initials: MT
authors.lastname: So
authors.forename: Guo
authors.initials: G
authors.lastname: Cheng
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Miao
authors.forename: Thomas Yuk-Yu
authors.initials: TY
authors.lastname: Leon
authors.forename: Brian Man-Chun
authors.initials: BM
authors.lastname: Leung
authors.forename: Kenneth-Jeremy W S
authors.initials: KJ
authors.lastname: Hui
authors.forename: Vincent Hang-Chai
authors.initials: VH
authors.lastname: Lui
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Ivy Hau-Yee
authors.initials: IH
authors.lastname: Chan
authors.forename: Patrick Ho-Yu
authors.initials: PH
authors.lastname: Chung
authors.forename: Xue-Lai
authors.initials: XL
authors.lastname: Liu
authors.forename: Kenneth Kak-Yuen
authors.initials: KK
authors.lastname: Wong
authors.forename: Pak-Chung
authors.initials: PC
authors.lastname: Sham
authors.forename: Stacey S
authors.initials: SS
authors.lastname: Cherny
authors.forename: Paul Kwong-Hang
authors.initials: PK
authors.lastname: Tam
authors.forename: Maria-Mercè
authors.initials: MM
authors.lastname: Garcia-Barcelo
mesh_terms: D000818:Animals; D019556:COS Cells; D016022:Case-Control Studies; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D006627:Hirschsprung Disease / Q000235:genetics*; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D008297:Male; D009154:Mutation / Q000235:genetics*; D020890:Neuregulin-1 / Q000235:genetics*
chemical_list: C094131:NRG1 protein, human; D020890:Neuregulin-1