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Article: Exome sequencing identifies novel compound heterozygous mutations of IL-10 receptor 1 in neonatal-onset Crohn’s disease
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TitleExome sequencing identifies novel compound heterozygous mutations of IL-10 receptor 1 in neonatal-onset Crohn’s disease
 
AuthorsMao, H1
Yang, W1
Lee, PPW1
Ho, MHK1
Yang, J1
Zeng, S1
Chong, CY1
Lee, TL1
Tu, W1
Lau, YL1
 
KeywordsInterleukin 10 receptor
Crohn disease
Exome
Gene sequence
Heterozygosity
 
Issue Date2012
 
PublisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/gene
 
CitationGenes and Immunity, 2012, v. 13 n. 5, p. 437-442 [How to Cite?]
DOI: http://dx.doi.org/10.1038/gene.2012.8
 
AbstractInflammatory bowel disease is well recognized for a strong genetic involvement in its pathogenesis. Homozygous mutations in interleukin-10 receptor 1 (IL-10R1) identified by linkage analysis were shown to be involved in this disorder. However, the underlying molecular mechanism and the causal nature of the mutations in the disease process remain to be clarified. In this study, using whole exome sequencing, we identified novel compound heterozygous missense mutations in the extracellular domain of IL-10R1 in a Crohn's disease patient from a non-consanguineous family. These mutations did not affect IL-10R1 expression, nor IL-10 binding. However, they abrogated IL-10R1 phosphorylation induced by IL-10, therefore leading to impaired STAT3 activation and suppression of inflammatory responses. After reconstitution with wild-type IL-10R1, the patient cells showed fully restored IL-10R function including IL-10-induced STAT3 activation and expression of suppressor of cytokine signaling 3. Thus, our results demonstrated that the mutations in IL-10R1 extracellular domain impair IL-10R1 activation rather than IL-10 binding, indicating these residues are important in IL-10 signal transduction through IL-10R1. The reconstitution data also confirmed the causality of the IL-10R1 mutations.
 
ISSN1466-4879
2012 Impact Factor: 3.675
2012 SCImago Journal Rankings: 1.365
 
DOIhttp://dx.doi.org/10.1038/gene.2012.8
 
ReferencesReferences in Scopus
 
DC FieldValue
dc.contributor.authorMao, H
 
dc.contributor.authorYang, W
 
dc.contributor.authorLee, PPW
 
dc.contributor.authorHo, MHK
 
dc.contributor.authorYang, J
 
dc.contributor.authorZeng, S
 
dc.contributor.authorChong, CY
 
dc.contributor.authorLee, TL
 
dc.contributor.authorTu, W
 
dc.contributor.authorLau, YL
 
dc.date.accessioned2012-04-20T02:05:07Z
 
dc.date.available2012-04-20T02:05:07Z
 
dc.date.issued2012
 
dc.description.abstractInflammatory bowel disease is well recognized for a strong genetic involvement in its pathogenesis. Homozygous mutations in interleukin-10 receptor 1 (IL-10R1) identified by linkage analysis were shown to be involved in this disorder. However, the underlying molecular mechanism and the causal nature of the mutations in the disease process remain to be clarified. In this study, using whole exome sequencing, we identified novel compound heterozygous missense mutations in the extracellular domain of IL-10R1 in a Crohn's disease patient from a non-consanguineous family. These mutations did not affect IL-10R1 expression, nor IL-10 binding. However, they abrogated IL-10R1 phosphorylation induced by IL-10, therefore leading to impaired STAT3 activation and suppression of inflammatory responses. After reconstitution with wild-type IL-10R1, the patient cells showed fully restored IL-10R function including IL-10-induced STAT3 activation and expression of suppressor of cytokine signaling 3. Thus, our results demonstrated that the mutations in IL-10R1 extracellular domain impair IL-10R1 activation rather than IL-10 binding, indicating these residues are important in IL-10 signal transduction through IL-10R1. The reconstitution data also confirmed the causality of the IL-10R1 mutations.
 
dc.description.natureLink_to_subscribed_fulltext
 
dc.identifier.citationGenes and Immunity, 2012, v. 13 n. 5, p. 437-442 [How to Cite?]
DOI: http://dx.doi.org/10.1038/gene.2012.8
 
dc.identifier.citeulike10543760
 
dc.identifier.doihttp://dx.doi.org/10.1038/gene.2012.8
 
dc.identifier.eissn1476-5470
 
dc.identifier.epage442
 
dc.identifier.hkuros200700
 
dc.identifier.issn1466-4879
2012 Impact Factor: 3.675
2012 SCImago Journal Rankings: 1.365
 
dc.identifier.issue5
 
dc.identifier.pmid22476154
 
dc.identifier.scopuseid_2-s2.0-84864118162
 
dc.identifier.spage437
 
dc.identifier.urihttp://hdl.handle.net/10722/146338
 
dc.identifier.volume13
 
dc.languageeng
 
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/gene
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofGenes and Immunity
 
dc.relation.referencesReferences in Scopus
 
dc.subjectInterleukin 10 receptor
 
dc.subjectCrohn disease
 
dc.subjectExome
 
dc.subjectGene sequence
 
dc.subjectHeterozygosity
 
dc.titleExome sequencing identifies novel compound heterozygous mutations of IL-10 receptor 1 in neonatal-onset Crohn’s disease
 
dc.typeArticle
 
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Author Affiliations
  1. The University of Hong Kong