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Article: Mutations in the NRG1 gene are associated with Hirschsprung disease
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TitleMutations in the NRG1 gene are associated with Hirschsprung disease
 
AuthorsTang, 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 Date2012
 
PublisherSpringer Verlag. The Journal's web site is located at http://link.springer.de/link/service/journals/00439/index.htm
 
CitationHuman Genetics, 2012, v. 131 n. 1, p. 67-76 [How to Cite?]
DOI: http://dx.doi.org/10.1007/s00439-011-1035-4
 
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.
 
ISSN0340-6717
2012 Impact Factor: 4.633
2012 SCImago Journal Rankings: 1.563
 
DOIhttp://dx.doi.org/10.1007/s00439-011-1035-4
 
ISI Accession Number IDWOS:000298659800005
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.

 
ReferencesReferences in Scopus
 
GrantsFunctional 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?
 
DC FieldValue
dc.contributor.authorTang, CSM
 
dc.contributor.authorNgan, ESW
 
dc.contributor.authorTang, WK
 
dc.contributor.authorSo, MT
 
dc.contributor.authorCheng, G
 
dc.contributor.authorMiao, XP
 
dc.contributor.authorLeon, TYY
 
dc.contributor.authorLeung, BMC
 
dc.contributor.authorHui, KJWS
 
dc.contributor.authorLui, VHC
 
dc.contributor.authorChen, Y
 
dc.contributor.authorChan, IHY
 
dc.contributor.authorChung, PHY
 
dc.contributor.authorLiu, XL
 
dc.contributor.authorWong, KKY
 
dc.contributor.authorSham, PC
 
dc.contributor.authorCherny, SS
 
dc.contributor.authorTam, PKH
 
dc.contributor.authorGarciaBarcelo, MM
 
dc.date.accessioned2012-02-03T06:14:27Z
 
dc.date.available2012-02-03T06:14:27Z
 
dc.date.issued2012
 
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.
 
dc.description.naturelink_to_subscribed_fulltext
 
dc.identifier.citationHuman 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.citeulike9487200
 
dc.identifier.doihttp://dx.doi.org/10.1007/s00439-011-1035-4
 
dc.identifier.eissn1432-1203
 
dc.identifier.epage76
 
dc.identifier.hkuros198431
 
dc.identifier.isiWOS:000298659800005
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.

 
dc.identifier.issn0340-6717
2012 Impact Factor: 4.633
2012 SCImago Journal Rankings: 1.563
 
dc.identifier.issue1
 
dc.identifier.pmid21706185
 
dc.identifier.scopuseid_2-s2.0-84856678164
 
dc.identifier.spage67
 
dc.identifier.urihttp://hdl.handle.net/10722/144570
 
dc.identifier.volume131
 
dc.languageeng
 
dc.publisherSpringer Verlag. The Journal's web site is located at http://link.springer.de/link/service/journals/00439/index.htm
 
dc.publisher.placeGermany
 
dc.relation.ispartofHuman Genetics
 
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.relation.referencesReferences in Scopus
 
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 disease
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong
  2. Huazhong University of Science and Technology