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
2011 Impact Factor: 3.872
2011 SCImago Journal Rankings: 0.631
DOIhttp://dx.doi.org/10.1038/gene.2012.8
ReferencesReferences in Scopus
DC Field
Value
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
2011 Impact Factor: 3.872
2011 SCImago Journal Rankings: 0.631
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
Author Affiliations
  1. The University of Hong Kong