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Article: Exome sequencing identifies novel compound heterozygous mutations of IL-10 receptor 1 in neonatal-onset Crohn’s disease

TitleExome sequencing identifies novel compound heterozygous mutations of IL-10 receptor 1 in neonatal-onset Crohn’s disease
Authors
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
Citation
Genes and Immunity, 2012, v. 13 n. 5, p. 437-442 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/146338
ISSN
2014 Impact Factor: 2.913
2014 SCImago Journal Rankings: 1.528
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorMao, Hen_HK
dc.contributor.authorYang, Wen_HK
dc.contributor.authorLee, PPWen_HK
dc.contributor.authorHo, MHKen_HK
dc.contributor.authorYang, Jen_HK
dc.contributor.authorZeng, Sen_HK
dc.contributor.authorChong, CYen_HK
dc.contributor.authorLee, TLen_HK
dc.contributor.authorTu, Wen_HK
dc.contributor.authorLau, YLen_HK
dc.date.accessioned2012-04-20T02:05:07Z-
dc.date.available2012-04-20T02:05:07Z-
dc.date.issued2012en_HK
dc.identifier.citationGenes and Immunity, 2012, v. 13 n. 5, p. 437-442en_HK
dc.identifier.issn1466-4879en_HK
dc.identifier.urihttp://hdl.handle.net/10722/146338-
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.en_HK
dc.languageengen_US
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/geneen_HK
dc.relation.ispartofGenes and Immunityen_HK
dc.subjectInterleukin 10 receptoren_HK
dc.subjectCrohn diseaseen_HK
dc.subjectExomeen_HK
dc.subjectGene sequenceen_HK
dc.subjectHeterozygosityen_HK
dc.titleExome sequencing identifies novel compound heterozygous mutations of IL-10 receptor 1 in neonatal-onset Crohn’s diseaseen_HK
dc.typeArticleen_HK
dc.identifier.emailMao, H: hwmau@hku.hken_HK
dc.identifier.emailYang, W: yangwl@hkucc.hku.hk-
dc.identifier.emailLee, PPW: ppwlee@hku.hk-
dc.identifier.emailHo, MHK: marcoho@hku.hk-
dc.identifier.emailYang, J: jingy09@hku.hk-
dc.identifier.emailLee, TL: leetsz@hkucc.hku.hk-
dc.identifier.emailTu, W: wwtu@hku.hk-
dc.identifier.emailLau, YL: lauylung@hku.hk-
dc.identifier.authorityLau, YL=rp00361en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1038/gene.2012.8en_HK
dc.identifier.pmid22476154-
dc.identifier.scopuseid_2-s2.0-84864118162en_HK
dc.identifier.hkuros200700-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84864118162&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume13en_HK
dc.identifier.issue5en_HK
dc.identifier.spage437en_HK
dc.identifier.epage442en_HK
dc.identifier.eissn1476-5470-
dc.identifier.isiWOS:000306587600009-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridLau, YL=7201403380en_HK
dc.identifier.scopusauthoridTu, W=55267176800en_HK
dc.identifier.scopusauthoridLee, TL=35573927500en_HK
dc.identifier.scopusauthoridChong, CY=55319454100en_HK
dc.identifier.scopusauthoridZeng, S=55319030800en_HK
dc.identifier.scopusauthoridYang, J=53664678600en_HK
dc.identifier.scopusauthoridHo, MHK=36554116300en_HK
dc.identifier.scopusauthoridLee, PPW=54782819300en_HK
dc.identifier.scopusauthoridYang, W=55319348000en_HK
dc.identifier.scopusauthoridMao, H=55319040700en_HK
dc.identifier.citeulike10543760-

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