Abstract
Inflammatory 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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 6 digital issues and online access to articles
$119.00 per year
only $19.83 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Baumgart DC, Sandborn WJ . Inflammatory bowel disease: clinical aspects and established and evolving therapies. Lancet 2007; 369: 1641–1657.
Baumgart DC, Carding SR . Inflammatory bowel disease: cause and immunobiology. Lancet 2007; 369: 1627–1640.
Abraham C, Cho JH . Inflammatory bowel disease. N Engl J Med 2009; 361: 2066–2078.
Franke A, McGovern DP, Barrett JC, Wang K, Radford-Smith GL, Ahmad T et al. Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nat Genet 2010; 42: 1118–1125.
Bolze A, Byun M, McDonald D, Morgan NV, Abhyankar A, Premkumar L et al. Whole-exome-sequencing-based discovery of human FADD deficiency. Am J Hum Genet 2010; 87: 873–881.
Byun M, Abhyankar A, Lelarge V, Plancoulaine S, Palanduz A, Telhan L et al. Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma. J Exp Med 2010; 207: 2307–2312.
Maxmen A . Exome sequencing deciphers rare diseases. Cell 2011; 144: 635–637.
Wu C, Orozco C, Boyer J, Leglise M, Goodale J, Batalov S et al. BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources. Genome Biol 2009; 10: R130.
Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 2008; 40: 955–962.
Braun J, Wei B . Body traffic: ecology, genetics, and immunity in inflammatory bowel disease. Annu Rev Pathol 2007; 2: 401–429.
Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W . Interleukin-10-deficient mice develop chronic enterocolitis. Cell 1993; 75: 263–274.
Franke A, Balschun T, Karlsen TH, Sventoraityte J, Nikolaus S, Mayr G et al. Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat Genet 2008; 40: 1319–1323.
Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schaffer AA, Noyan F et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med 2009; 361: 2033–2045.
Begue B, Verdier J, Rieux-Laucat F, Goulet O, Morali A, Canioni D et al. Defective IL10 signaling defining a subgroup of patients with inflammatory bowel disease. Am J Gastroenterol 2011; 106: 1544–1555.
Makita S, Kanai T, Oshima S, Uraushihara K, Totsuka T, Sawada T et al. CD4+CD25bright T cells in human intestinal lamina propria as regulatory cells. J Immunol 2004; 173: 3119–3130.
Ouyang W, Rutz S, Crellin NK, Valdez PA, Hymowitz SG . Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu Rev Immunol 2011; 29: 71–109.
Josephson K, Logsdon NJ, Walter MR . Crystal structure of the IL-10/IL-10R1 complex reveals a shared receptor binding site. Immunity 2001; 15: 35–46.
Pletnev S, Magracheva E, Wlodawer A, Zdanov A . A model of the ternary complex of interleukin-10 with its soluble receptors. BMC Struct Biol 2005; 5: 10.
Williams L, Bradley L, Smith A, Foxwell B . Signal transducer and activator of transcription 3 is the dominant mediator of the anti-inflammatory effects of IL-10 in human macrophages. J Immunol 2004; 172: 567–576.
Finsterbusch M, Khare V, Campregher C, Evstatiev R, Gasche C . An intracytoplasmic IL-10 receptor variant permits rapid reduction in STAT3 activation. Genes Immun 2011; 12: 575–581.
Grundtner P, Gruber S, Murray SS, Vermeire S, Rutgeerts P, Decker T et al. The IL-10R1 S138G loss-of-function allele and ulcerative colitis. Genes Immun 2009; 10: 84–92.
Donnelly RP, Dickensheets H, Finbloom DS . The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes. J Interferon Cytokine Res 1999; 19: 563–573.
Cho JH, Brant SR . Recent insights into the genetics of inflammatory bowel disease. Gastroenterology 2011; 140: 1704–1712.
Ghaith OA, El Halabi MM, Abdul-Baki H, Gasche C, Nemeth M, Sharara AI . Lack of correlation between IL-10R1 S138G loss-of-function allele and IBD in the Lebanese population. Inflamm Bowel Dis 2010; 16: 1819–1820.
Bamshad MJ, Ng SB, Bigham AW, Tabor HK, Emond MJ, Nickerson DA et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat Rev Genet 2011; 12: 745–755.
Acknowledgements
This work was supported by the Edward Sai-Kim Hotung Pediatric Education & Research Fund (YLL); and Chung Ko Lee and Cheung Yuen Kan Education & Research Fund in Paediatric Immunology (YLL). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on Genes and Immunity website
Supplementary information
Rights and permissions
About this article
Cite this article
Mao, H., Yang, W., Lee, P. et al. Exome sequencing identifies novel compound heterozygous mutations of IL-10 receptor 1 in neonatal-onset Crohn's disease. Genes Immun 13, 437–442 (2012). https://doi.org/10.1038/gene.2012.8
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/gene.2012.8
Keywords
This article is cited by
-
Clinical Features and Genetic Analysis of Taiwanese Primary Immunodeficiency Patients with Prolonged Diarrhea and Monogenetic Inflammatory Bowel Disease
Journal of Clinical Immunology (2023)
-
The monogenic basis of human tuberculosis
Human Genetics (2020)
-
Gastrointestinal Disorders Associated with Primary Immunodeficiency Diseases
Clinical Reviews in Allergy & Immunology (2019)
-
A Nationwide Study of Severe and Protracted Diarrhoea in Patients with Primary Immunodeficiency Diseases
Scientific Reports (2017)
-
Exome Analysis of Rare and Common Variants within the NOD Signaling Pathway
Scientific Reports (2017)