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


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.


Crohn's disease (CD) is a type of inflammatory bowel disease, which can present at any age, but is most commonly diagnosed in the adolescent and young adults. With the advances in the understanding of immunopathogenesis of this disease, a series of biological therapies targeting distinct relevant pathways have been developed, including suppression of TNF-α, modulation of other cytokines and blockade of inflammatory cell migration.1 Although these approaches improve significantly the outcome of patients, some cases are still refractory to standard treatment. A better understanding of the mechanisms may lead to novel approaches in the therapeutics.

Familial aggregation, high concordance in twins and higher prevalence of the disease in a particular ethnic population all support genetic contribution to the development of the disease.2 However, the genetic factors for CD remain poorly understood. Identifying the disease-associated susceptibility genes or the causal mutations in certain cases will undoubtedly help elucidate the pathogenesis of the disease and facilitate the development of more targeted therapy. Recent successes in genome-wide association study have uncovered a total of 71 loci associated with CD to date, including components of both innate and adaptive immunity.3, 4 Although these findings provide valuable insight to the immunopathogenesis of CD, the common alleles only explain 23% of the total genetic risk factors.4 Rare variants may also have vital roles in the disease, especially that with extreme phenotypes.

Classical linkage analysis has an important role in detecting causal mutations of genetic diseases in consanguineous families, but provides limited usefulness in the outbred populations. The whole exome sequencing is not limited by the availability of family data and can be performed on merely one or a few affected individuals for molecular detection of causal mutations. There are at least 128 exomes that have been sequenced with 39 rare disorders diagnosed.5, 6, 7 In this study, using whole exome sequencing, we identified novel compound heterozygous mutations of interleukin-10 receptor 1 (IL-10R1) extracellular domain in a child with neonatal-onset CD from a non-consanguineous family. The dysfunction of IL-10R1 signaling and the underlying molecular mechanism were clarified.

Results and discussion

Identification of novel compound heterozygous mutations in the extracellular domain of IL-10R1

The patient was delivered at full term from a non-consanguineous family. Since second week of life, he began to present with CD symptoms. Colonoscopy showed colitis involving rectum, sigmoid colon and descending colon, and biopsy showed non-specific inflammation. He had severe growth failure and was finally managed as a case of CD. He received multiple therapies including immunosuppressive drugs and infliximab for refractory disease at various times. Bone marrow transplant was refused by the parents. He is now 3.5-years old in remission on a combination of low dose prednisolone, azathioprine, methotrexate and infliximab. The detailed patient history is provided in the Supplementary Information.

We performed whole exome sequencing for the patient and his parents using Illumina Genome Analyzer IIx (Illumina, San Diego, CA, USA) in the middle of 2009. For the targeted sequences, we only considered regions with 10-fold coverage or above in order to filter out poor quality variants. This would significantly reduce call errors and only cause 5% coverage loss (from 95 to 90%) of the target regions. As shown in Table 1, we detected a total of 26 648 genetic variants in the patient, including both point mutations and indels. A step-wise approach was taken to help narrow down the list of genetic variants to be considered for this disease. We first tagged the genetic variants existing in dbSNP (build 132) and 1000 Genome Project as low-priority variants for this disease. Similarly, we tagged the coding synonymous mutations and variants in intergenic regions, introns and UTRs as less likely to be disease causal, despite reports of causal nature for variants in those regions. For the point mutations, we focused our attention on the nonsynonymous changes, splicing variants (within 2 bp of a splicing junction), and coding indels. Their potential to be functionally damaging was also considered based on the programs on the bases of sequence conservation during evolutionary courses. For homozygous mutations in the patient, we only focused on the ones on which neither parents are homozygous on the mutant allele. For heterozygous mutations, we focused on those compound heterozygous in nature. The detailed information on exome sequencing and analysis is provided in the Supplementary Information. After the step-wise filtering procedure, 11 genes that contain either homozygous changes or compound heterozygous mutations were considered of particular interest genetically (Table 1).

Table 1 Step-wise analysis of mutations found in the patient

For the 11 genes, we analyzed their tissue distributions and functions using online tools BioGPS,8 Entrez Gene (http://www.ncbi.nlm.nih.gov/gene), UniProt (http://www.uniprot.org/) (Supplementary Table 1). Among them, no expression data are available for OR13C2, KRTAP19-6 and LOC497190, but the former two are involved in specific events other than immune response, and the latter one is related with sugar binding inferred from electronic annotation. The remaining eight genes except IL-10RA are expressed in multiple tissues evenly or with higher level in certain tissues, therefore, it could be expected that the mutations of these genes would not affect merely one tissue or only immune function. In contrast, IL-10RA is mainly expressed on immune cells at a high level. It mediates the immunosuppressive signal of interleukin 10 and thus inhibits the synthesis of proinflammatory cytokines (Supplementary Table 1). Considering the immunopathogenesis of CD, investigating IL-10RA among the total 11 genes would be the first priority for the disorder. CD is characterized by abnormal inflammation in genetically susceptible hosts.3 The exaggerated inflammatory responses caused by the interaction between host immunity and environmental microbes are believed to have a critical role in the pathogenesis of this disorder.3, 9, 10 IL-10 is well recognized as an important anti-inflammatory player for maintaining the homeostasis in the gut, suggestive of a role in the pathogenesis of CD. The finding that IL-10-deficient mice develop spontaneous enterocolitis further supports its contribution to this disease.3, 11 IL-10 gene is also known to be associated with ulcerative colitis, another type of inflammatory bowel disease.12 Therefore, taken together, we hypothesized that the compound heterozygous mutations in IL-10RA are the most likely causal mutations for the disease.

Sanger sequencing confirmed the heterozygous mutations of IL-10RA in the patient's father (c.251C>T, p.T84I) and mother (c.301C>T, p.R101W), and the compound heterozygous nature in the patient (Figure 1a) consistent with the original sequencing finding (Supplementary Figure 2). The two amino-acid residues are located in the extracellular domain of IL-10R1. The potential structural impact caused by the two mutations, T84I and R101W, was further analyzed by Swiss-PdbViewer (Swiss Institute of Bioinformatics; http://spdbv.vital-it.ch/). As shown in Figure 1b, a hydrogen bond present between Thr84 and His41 in the wild type IL-10R1 was broken by the Ile84 mutation. The Arg101Trp mutation not only disrupted two putative hydrogen bonds between Glu58 and Arg101 present in the wild-type IL-10R1, but also caused steric clashes between Trp101 and Glu58, Val103 and Trp111 in the variant, respectively. These structural changes might interfere with either stability of the protein, binding affinity of IL-10 or signal transduction.

Figure 1

Sequence and structural analysis of the mutant IL-10R1. (a) Sanger sequencing of IL-10RA confirmed the compound heterozygous mutations in the patient (c.251C>T, p.T84I; c.301C>T, p.R101W). The heterozygous carrier status of the parents was also verified. (b) The structural impact of the variants Thr84Ile (upper panel) and Arg101Trp (lower panel) was analyzed based on the template of 1Y6K from PDB. The residues 84 or 101, together with nearby residues within 6 Å, was illustrated in the wild-type (WT) and variant IL-10R1 by Swiss-PdbViewer. The computed hydrogen bonds are shown as green dashed lines and steric clashes as purple dashed lines. Residues Thr84/Ile84 and His41 were highlighted in pink and yellow respectively (upper panel). Residues Arg101/Trp101, Glu58, Val103 and Trp111 were highlighted in pink, yellow, dark blue and violet (lower panel).

The compound heterozygous mutations caused IL-10R1 dysfunction

Indeed, at around the time of our discovery, a group reported homozygous mutations of IL-10R1 extracellular domain (p.T84I or p.G141R) in CD using linkage analysis.13 Subsequently another group identified homozygous mutations in the intracellular domain (p.R262C) in IBD.14 Both of them showed the inability of mutant IL-10R1 to suppress inflammatory response. Herein for the novel compound heterozygous mutations (p.T84I and p.R101W) in the extracellular domain, we continued to evaluate their impact on IL-10R1 function. Individual peripheral blood mononuclear cells (PBMCs) were stimulated by LPS with or without IL-10, and the supernatants were examined for the production of cytokines and chemokines. Compared with those in the healthy controls and his heterozygous mutation-carrying parents, LPS induced much higher IL-1α, IL-1β, TNF-α and RANTES but comparable IL-10 productions in patient's PBMCs (Supplementary Figures 3 and 4). Human recombinant IL-10 significantly inhibited LPS-induced proinflammatory cytokine and chemokine productions, including TNF-α, IL-1β, IL-1α, IL-6, IFN-γ, MIP-1α, MIP-1β and RANTES in PBMCs from the controls and the parents, but had no such inhibitory effects in cells from the patient. As Foxp3+ T regulatory cells have been suggested to dampen inflammation in the inflammatory diseases,3, 15 we further examined the presence of natural T-regulatory cells in the patient. As shown in Supplementary Figure 5, a comparable level of Foxp3 expression in CD3+CD25+ T cells was observed between the patient and controls. Thus, these data showed the intact function of heterozygous mutation, suggesting the recessive nature of the mutation, which is compatible with the clinical phenotype that the patient presents with CD whereas the parents are otherwise healthy. In addition, like the reported homozygous mutations, the novel compound heterozygous mutations also impaired IL-10R1 function.

The compound heterozygous mutations impaired IL-10R1 signaling, but not IL-10 binding

Although the dysfunction caused by the aforementioned homozygous mutation has been shown, the underlying molecular mechanism remains unknown13, 14 (Supplementary Table 2). In this study, after the demonstration of defective IL-10R function, we further investigated the molecular mechanism. The functional IL-10 receptor consists of two chains: IL-10R1 and IL-10R2. IL-10R1 belongs to the class II cytokine receptor family and functions as a ligand-binding protein. IL-10R2 participates in the signal transduction. The binding of IL-10 to IL-10R activates two receptor-associated Janus tyrosine kinases, Jak1 and Tyk2, which in turn phosphorylate the specific tyrosine residues in the intracellular domain of IL-10R1. The residues function as docking sites for signal transducer and activator of transcription 3 (STAT3), which is then phosphorylated by the receptor-associated kinases and translocates to the nucleus to promote the expression of IL-10-responsive genes.16

Herein, we first examined the expression level of IL-10R. As shown in Figure 2a, the compound mutations did not affect the surface expressions of both IL-10R1 and IL-10R2. Considering IL-10R1 is a ligand-binding subunit and the mutant residues (p.T84I and p.R101W) are located in the extracellular domain of IL-10R1, we proposed the compound heterozygous mutations might interfere with IL-10 binding. However, the IL-10-binding ability of mutant IL-10R1 in the patient was demonstrated to be comparable to that of wild-type IL-10R1 in normal controls (Figure 2b), which is theoretically compatible with structural finding that the two variant amino-acid residues are not located in the IL-10-binding loops or IL-10R1/IL-10R2 interacting interface of IL-10R1.17, 18 Then we moved to examine the downstream signaling event. As shown in Figure 2c, upon IL-10 stimulation, the compound mutations impaired IL-10R1 activation in the patient cells, as evidenced by the absence of phosphorylation. In contrast, IL-10 induced IL-10R1 phosphorylation in the controls. As STAT3 activation upon IL-10 engagement is critical for the anti-inflammatory effects of IL-10,19 we further examined the STAT3 signaling in the patient and found that IL-10 ligation induced significant STAT3 phosphorylation in the controls and the parents. However, only a negligible level of STAT3 activation was observed in the patient cells (Figure 2d). Taken together, these compound heterozygous mutations in the extracellular domain of IL-10R1 did not affect IL-10R1 expression, nor IL-10 binding. However, they abrogated IL-10R1 activation induced by IL-10; therefore, leading to impaired STAT3 activation and finally the failure of anti-inflammatory effect of IL-10, which indicates these residues are important for IL-10 signal transduction through IL-10R1.

Figure 2

The compound heterozygous mutations impaired IL-10R1 signaling, but not IL-10 binding. (a) After pretreatment with FcR blocking reagent, individual PBMCs were examined for the surface expressions of IL-10R1 and IL-10R2 on monocytes by flow cytometry. (b) PBMCs were incubated with biotinylated IL-10 (IL-10) or soybean trypsin inhibitor (negative control) at 4 °C for 1 h. After further incubated with avidin-fluorescein, the cells were analyzed for IL-10 binding on monocytes by flow cytometry. (c) Individual PBMCs were stimulated with recombinant human IL-10 for 15 or 30 min and then determined for the intracellular expression of phospho-IL-10R1 (pIL-10R1) by flow cytometry. The increase in the percentage of pIL-10R1 expression in stimulated cells relative to resting cells was calculated. (d) PBMCs were stimulated with recombinant human IL-10 for 45 min and then examined for the intracellular expression of phospho-STAT3 (pSTAT3) by flow cytometry in monocytes (upper row) and B cells (lower row). The increase in the percentage of pSTAT3 expression in stimulated cells relative to resting cells was calculated. The data shown are representatives of three independent experiments.

Previous studies showed that a loss-of-function variant in IL-10R1 intracellular domain (p.G330R) caused rapid decline of STAT3 activation level20 post initial full induction of STAT3 phosphorylation.20, 21 These data suggested that the variant (p.G330R) did not affect the signaling events upstream to STAT3 activation including IL-10 binding and IL-10R1 activation, but other mechanisms contributed to the dysfunction of this variant. Herein, we found that the novel compound heterozygous mutations (p.T84I and p.R101W) abrogated IL-10R1 activation and led to impaired IL-10R function. Thus, it is suggested that the mutations in different regions may use distinct mechanisms to affect IL-10R1 function. Therefore, for the mechanisms of IL-10R dysfunction induced by the reported homozygous mutations in different sites, whether they are due to alteration of IL-10 binding, IL-10R1 activation or other mechanisms require further investigation.

Reconstitution of wild-type IL-10R1 fully restored the defective IL-10R function

For the homozygous mutations of IL-10 receptors identified in inflammatory bowel disease, a group has demonstrated the causality of IL-10R2 mutation via the rescue assay with wild-type IL-10R2 and bone marrow transplantation.13 However, the causal nature of IL-10R1 mutation remains to be clarified (Supplementary Table 2). In this study, after the demonstration of defective IL-10R1 signaling and the underlying mechanism, we further investigated whether the compound heterozygous mutations were the causal mutations responsible for the defective IL-10R1 signaling pathway. The rescue assay with wild-type IL-10R1 was performed in the patient’s cells. The wild-type IL-10R1-expressing lentivirus was produced with a bicistronic lentiviral vector pLVX-IRES-ZsGreen1 that expresses green fluorescence protein. The EBV-transformed B cells of the patient were infected with wild-type IL-10R1-expressing lentivirus and the successfully transduced cells were sorted (Figure 3a). After stimulation with IL-10, STAT3 phosphorylation in the sorted cells was determined. As indicated in Figure 3b, negligible activation of STAT3 was observed in the patient's original B cells, but the transduced cells showed significant phosphorylation of STAT3. The activation of STAT3 confirmed the normal functionality of IL-10 signaling pathway in the transduced cells.

Figure 3

Reconstitution of wild-type IL-10R1 fully restored the defective IL-10R function. (a) EBV-transformed B cells derived from the patient were infected with the wild-type human IL-10R1-expressing lentivirus. The successfully transduced cells were sorted by flow cytometry. Cells were observed under the fluorescence microscope. (b) The transduced cells were stimulated with IL-10 for 30 min and then determined for the intracellular expression of phospho-STAT3 (pSTAT3) by flow cytometry. The increase in the percentage of pSTAT3 expression in stimulated cells relative to resting cells was calculated. (c) Individual cells were stimulated with IL-10 for 1 h and then collected for total cellular RNA extraction. The cDNA was transcribed and examined for SOCS3 expression by quantitative PCR. The fold increase of SOCS3 expression in stimulated cells (IL-10) relative to that in unstimulated cells (Unsti) was calculated. The data shown are representatives of three independent experiments.

It has been demonstrated that IL-10 signaling-mediated STAT3 activation leads to the expressions of IL-10-responsive genes, of which, suppressor of cytokine signaling 3 (SOCS3) is an important member. The rapid synthesis of SOCS3 was reported to correlate with the ability of IL-10 to inhibit the expressions of cytokines including TNF-α and IL-1.22 Therefore, we further examined SOCS3 expression induced by IL-10 stimulation. As shown in Figure 3c, in response to IL-10 stimulation, little increase of SOCS3 expression was induced in the patient's original B cells. However, the transduced B cells showed a remarkable enhancement of SOCS3 expression after IL-10 stimulation. Taken together, these data clearly demonstrated the full restoration of defective IL-10R function by reconstitution of wild-type IL-10R1, confirming the causal nature of these IL-10R1 mutations for the defective IL-10R function.

For the uncommon variants that contribute to complex diseases such as IBD, considering population differences will be particularly important, as less common alleles are more likely to be population specific.23 The correlation of a SNP of IL-10R1 with IBD was demonstrated in some ethnic populations but not in others.21, 24 Therefore, besides the discovery in European and Lebanese,13, 14 it is useful to examine the rare variants of IL-10R in neonatal-onset IBD in other populations. In this study we further identified such rare variant in the Han Chinese. Its prevalence in Chinese IBD patients will be further investigated. The information on the prevalence of IL-10R mutation in distinct ethnic populations and the resulting comparative insights will significantly improve our understanding of the genetics of neonatal-onset IBD.

Linkage analysis is traditionally used to identify gene mutations of genetic disorders in families of consanguineous marriages. Although homozygous recessive mutations are the major type of mutations in consanguineous families, compound heterozygous mutations may be more common in outbred populations. It could just be a reflection of the difficulties in their discovery that not many compound heterozygous mutations were detected so far. Classical linkage method, such as homozygosity mapping, is unable to detect compound heterozygous mutations in sporadic cases. With the advances of next generation sequencing technology, whole exome sequencing provides an efficient approach for molecular detection of causal mutations. It is often used with sampling of extreme phenotypes where the individuals are at ends of a phenotype distribution. As the frequency of alleles contributing to the trait are enriched in the extremes of a distribution, sequencing the exome of even one or a few affected individuals can potentially identify novel alleles for rare diseases.25 Herein, we used exome sequencing to successfully identify novel compound heterozygous mutations in a patient with extreme phenotype of a complex disease (neonatal-onset CD) from a non-consanguineous family, which highlights the power of exome sequencing in detecting such causal mutations in the extreme phenotype study design. It is envisaged that exome or whole genome sequencing will have more and more important roles in clinical diagnosis of monogenic deficiency.

In summary, in this study, novel compound heterozygous mutations of IL-10R1 were identified in neonatal-onset CD in the Han Chinese. Besides the demonstration of defective IL-10R1 function, we further clarified the underlying molecular mechanism. The mutations in IL-10R1 extracellular domain did not affect IL-10 binding, but impaired IL-10 signal transduction through IL-10R1, as evidenced by the lack of IL-10R1 activation, which therefore led to impaired STAT3 activation and finally the failure of anti-inflammatory effect of IL-10. The data indicated that these residues are important for IL-10 signal transduction. The reconstitution data confirmed the causality of these IL-10R1 mutations. This study also demonstrated the advantage of exome sequencing in identifying compound heterozygous mutations.


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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.

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Correspondence to W Tu or Y-L Lau.

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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

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  • exome sequencing
  • IL-10 receptor 1
  • compound heterozygous mutations
  • IL-10 receptor 1 signaling
  • IL-10 binding
  • Crohn's disease

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