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Article: Mutations in the NRG1 gene are associated with Hirschsprung disease

TitleMutations in the NRG1 gene are associated with Hirschsprung disease
Authors
Issue Date2012
PublisherSpringer 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?
AbstractHirschsprung 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.
Persistent Identifierhttp://hdl.handle.net/10722/144570
ISSN
2014 Impact Factor: 4.824
2014 SCImago Journal Rankings: 2.261
ISI Accession Number ID
Funding AgencyGrant Number
Hong Kong Research Grants CouncilHKU 765407M
765609M
HKU778610M
HKU 775710M
University of Hong Kong200911159071
200910159040
200811159006
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
Grants

 

DC FieldValueLanguage
dc.contributor.authorTang, CSMen_HK
dc.contributor.authorNgan, ESWen_HK
dc.contributor.authorTang, WKen_HK
dc.contributor.authorSo, MTen_HK
dc.contributor.authorCheng, Gen_HK
dc.contributor.authorMiao, XPen_HK
dc.contributor.authorLeon, TYYen_HK
dc.contributor.authorLeung, BMCen_HK
dc.contributor.authorHui, KJWSen_HK
dc.contributor.authorLui, VHCen_HK
dc.contributor.authorChen, Yen_HK
dc.contributor.authorChan, IHYen_HK
dc.contributor.authorChung, HYen_HK
dc.contributor.authorLiu, XLen_HK
dc.contributor.authorWong, KKYen_HK
dc.contributor.authorSham, PCen_HK
dc.contributor.authorCherny, SSen_HK
dc.contributor.authorTam, PKHen_HK
dc.contributor.authorGarciaBarcelo, MMen_HK
dc.date.accessioned2012-02-03T06:14:27Z-
dc.date.available2012-02-03T06:14:27Z-
dc.date.issued2012en_HK
dc.identifier.citationHuman Genetics, 2012, v. 131 n. 1, p. 67-76en_HK
dc.identifier.issn0340-6717en_HK
dc.identifier.urihttp://hdl.handle.net/10722/144570-
dc.description.abstractHirschsprung 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.en_HK
dc.languageengen_US
dc.publisherSpringer Verlag. The Journal's web site is located at http://link.springer.de/link/service/journals/00439/index.htmen_HK
dc.relation.ispartofHuman Geneticsen_HK
dc.rightsThe original publication is available at www.springerlink.com-
dc.subject.meshCOS Cells-
dc.subject.meshGenotype-
dc.subject.meshHirschsprung Disease - genetics-
dc.subject.meshMutation - genetics-
dc.subject.meshNeuregulin-1 - genetics-
dc.titleMutations in the NRG1 gene are associated with Hirschsprung diseaseen_HK
dc.typeArticleen_HK
dc.identifier.emailNgan, ESW: engan@hku.hken_HK
dc.identifier.emailTang, WK: evelynt@hku.hken_HK
dc.identifier.emailLui, VHC: vchlui@hku.hken_HK
dc.identifier.emailChen, Y: ychenc@hku.hken_HK
dc.identifier.emailWong, KKY: kkywong@hku.hken_HK
dc.identifier.emailSham, PC: pcsham@hku.hken_HK
dc.identifier.emailCherny, SS: cherny@hku.hken_HK
dc.identifier.emailTam, PKH: paultam@hku.hken_HK
dc.identifier.emailGarciaBarcelo, MM: mmgarcia@hku.hken_HK
dc.identifier.authorityNgan, ESW=rp00422en_HK
dc.identifier.authorityTang, WK=rp01629en_HK
dc.identifier.authorityLui, VHC=rp00363en_HK
dc.identifier.authorityChen, Y=rp01318en_HK
dc.identifier.authorityWong, KKY=rp01392en_HK
dc.identifier.authoritySham, PC=rp00459en_HK
dc.identifier.authorityCherny, SS=rp00232en_HK
dc.identifier.authorityTam, PKH=rp00060en_HK
dc.identifier.authorityGarciaBarcelo, MM=rp00445en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1007/s00439-011-1035-4en_HK
dc.identifier.pmid21706185en_HK
dc.identifier.scopuseid_2-s2.0-84856678164en_HK
dc.identifier.hkuros198431en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84856678164&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume131en_HK
dc.identifier.issue1en_HK
dc.identifier.spage67en_HK
dc.identifier.epage76en_HK
dc.identifier.eissn1432-1203-
dc.identifier.isiWOS:000298659800005-
dc.publisher.placeGermanyen_HK
dc.relation.projectFunctional evaluation of RET coding and non-coding sequence mutations in Hirschsprung's disease-
dc.relation.projectPremature gliogenesis of enteric neural crest cells induced by aberrant Sonic hedgehog-Notch signalling: a cause of Hirschsprung disease?-
dc.identifier.scopusauthoridTang, CSM=35764635500en_HK
dc.identifier.scopusauthoridNgan, ESW=22234827500en_HK
dc.identifier.scopusauthoridTang, WK=37462250200en_HK
dc.identifier.scopusauthoridSo, MT=8748542200en_HK
dc.identifier.scopusauthoridCheng, G=37861100700en_HK
dc.identifier.scopusauthoridMiao, XP=7102585391en_HK
dc.identifier.scopusauthoridLeon, TYY=10641704600en_HK
dc.identifier.scopusauthoridLeung, BMC=37461707700en_HK
dc.identifier.scopusauthoridHui, KJWS=35764515100en_HK
dc.identifier.scopusauthoridLui, VHC=7004231344en_HK
dc.identifier.scopusauthoridChen, Y=36463185300en_HK
dc.identifier.scopusauthoridChan, IHY=36344597900en_HK
dc.identifier.scopusauthoridChung, PHY=34568741300en_HK
dc.identifier.scopusauthoridLiu, XL=37461750900en_HK
dc.identifier.scopusauthoridWong, KKY=24438686400en_HK
dc.identifier.scopusauthoridSham, PC=34573429300en_HK
dc.identifier.scopusauthoridCherny, SS=7004670001en_HK
dc.identifier.scopusauthoridTam, PKH=7202539421en_HK
dc.identifier.scopusauthoridGarciaBarcelo, MM=6701767303en_HK
dc.identifier.citeulike9487200-

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