Article: Mutations in the NRG1 gene are associated with Hirschsprung disease
| Title | Mutations in the NRG1 gene are associated with Hirschsprung disease | ||||||
|---|---|---|---|---|---|---|---|
| Authors | Tang, CSM1 Ngan, ESW1 Tang, WK1 So, MT1 Cheng, G1 Miao, XP2 Leon, TYY1 Leung, BMC1 Hui, KJWS1 Lui, VHC1 Chen, Y1 Chan, IHY1 Chung, PHY1 Liu, XL1 Wong, KKY1 Sham, PC1 Cherny, SS1 Tam, PKH1 GarciaBarcelo, MM1 | ||||||
| Issue Date | 2012 | ||||||
| Publisher | Springer Verlag. The Journal's web site is located at http://link.springer.de/link/service/journals/00439/index.htm | ||||||
| Citation | Human Genetics, 2012, v. 131 n. 1, p. 67-76 [How to Cite?] DOI: http://dx.doi.org/10.1007/s00439-011-1035-4 | ||||||
| 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. © 2011 Springer-Verlag. | ||||||
| ISSN | 0340-6717 2011 Impact Factor: 5.069 2011 SCImago Journal Rankings: 0.328 | ||||||
| DOI | http://dx.doi.org/10.1007/s00439-011-1035-4 | ||||||
| ISI Accession Number ID | WOS:000298659800005
Funding Information: This work was supported by research grants from the Hong Kong Research Grants Council HKU 765407M and 765609M to MGB, HKU778610M to PT and HKU 775710M to ESWN; and from The University of Hong Kong Seed Funding Programme 200911159071 to PT and 200910159040 and 200811159006 to MGB. Support was also obtained from The University of Hong Kong Genomics Strategic Research Theme. | ||||||
| References | References in Scopus | ||||||
| Grants | NRG1 intron 1 SNPs in Hirschsprung's disease Sequencing of the neuregulin-1 (NRG1) gene in Hisrchprung's disease patients Functional evaluation of RET coding and non-coding sequence mutations in Hirschsprung's disease Premature gliogenesis of enteric neural crest cells induced by aberrant Sonic hedgehog-Notch signalling: a cause of Hirschsprung disease? Functional characterization of the V226L, H347Y, and P356L NRG1 mutations identified in Hirschsprung's disease patients |
| dc.contributor.author | Tang, CSM | ||||||
|---|---|---|---|---|---|---|---|
| dc.contributor.author | Ngan, ESW | ||||||
| dc.contributor.author | Tang, WK | ||||||
| dc.contributor.author | So, MT | ||||||
| dc.contributor.author | Cheng, G | ||||||
| dc.contributor.author | Miao, XP | ||||||
| dc.contributor.author | Leon, TYY | ||||||
| dc.contributor.author | Leung, BMC | ||||||
| dc.contributor.author | Hui, KJWS | ||||||
| dc.contributor.author | Lui, VHC | ||||||
| dc.contributor.author | Chen, Y | ||||||
| dc.contributor.author | Chan, IHY | ||||||
| dc.contributor.author | Chung, PHY | ||||||
| dc.contributor.author | Liu, XL | ||||||
| dc.contributor.author | Wong, KKY | ||||||
| dc.contributor.author | Sham, PC | ||||||
| dc.contributor.author | Cherny, SS | ||||||
| dc.contributor.author | Tam, PKH | ||||||
| dc.contributor.author | GarciaBarcelo, MM | ||||||
| dc.date.accessioned | 2012-02-03T06:14:27Z | ||||||
| dc.date.available | 2012-02-03T06:14:27Z | ||||||
| dc.date.issued | 2012 | ||||||
| dc.description.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. © 2011 Springer-Verlag. | ||||||
| dc.description.grant | NRG1 intron 1 SNPs in Hirschsprung's disease | ||||||
| dc.description.grant | Sequencing of the neuregulin-1 (NRG1) gene in Hisrchprung's disease patients | ||||||
| dc.description.grant | Functional evaluation of RET coding and non-coding sequence mutations in Hirschsprung's disease | ||||||
| dc.description.grant | Premature gliogenesis of enteric neural crest cells induced by aberrant Sonic hedgehog-Notch signalling: a cause of Hirschsprung disease? | ||||||
| dc.description.grant | Functional characterization of the V226L, H347Y, and P356L NRG1 mutations identified in Hirschsprung's disease patients | ||||||
| dc.description.grantcode | 101817 | ||||||
| dc.description.grantcode | 99882 | ||||||
| dc.description.grantcode | 96818 | ||||||
| dc.description.grantcode | 103534 | ||||||
| dc.description.grantcode | 101813 | ||||||
| dc.description.nature | link_to_subscribed_fulltext | ||||||
| dc.identifier.citation | Human Genetics, 2012, v. 131 n. 1, p. 67-76 [How to Cite?] DOI: http://dx.doi.org/10.1007/s00439-011-1035-4 | ||||||
| dc.identifier.citeulike | 9487200 | ||||||
| dc.identifier.doi | http://dx.doi.org/10.1007/s00439-011-1035-4 | ||||||
| dc.identifier.epage | 76 | ||||||
| dc.identifier.hkuros | 198431 | ||||||
| dc.identifier.isi | WOS:000298659800005
Funding Information: This work was supported by research grants from the Hong Kong Research Grants Council HKU 765407M and 765609M to MGB, HKU778610M to PT and HKU 775710M to ESWN; and from The University of Hong Kong Seed Funding Programme 200911159071 to PT and 200910159040 and 200811159006 to MGB. Support was also obtained from The University of Hong Kong Genomics Strategic Research Theme. | ||||||
| dc.identifier.issn | 0340-6717 2011 Impact Factor: 5.069 2011 SCImago Journal Rankings: 0.328 | ||||||
| dc.identifier.issue | 1 | ||||||
| dc.identifier.pmid | 21706185 | ||||||
| dc.identifier.scopus | eid_2-s2.0-84856678164 | ||||||
| dc.identifier.spage | 67 | ||||||
| dc.identifier.uri | http://hdl.handle.net/10722/144570 | ||||||
| dc.identifier.volume | 131 | ||||||
| dc.language | eng | ||||||
| dc.publisher | Springer Verlag. The Journal's web site is located at http://link.springer.de/link/service/journals/00439/index.htm | ||||||
| dc.publisher.place | Germany | ||||||
| dc.relation.ispartof | Human Genetics | ||||||
| dc.relation.references | References in Scopus | ||||||
| dc.rights | The original publication is available at www.springerlink.com | ||||||
| dc.subject.mesh | COS Cells | ||||||
| dc.subject.mesh | Genotype | ||||||
| dc.subject.mesh | Hirschsprung Disease - genetics | ||||||
| dc.subject.mesh | Mutation - genetics | ||||||
| dc.subject.mesh | Neuregulin-1 - genetics | ||||||
| dc.title | Mutations in the NRG1 gene are associated with Hirschsprung disease | ||||||
| dc.type | Article |
Author Affiliations
- The University of Hong Kong
- Huazhong University of Science and Technology