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

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.

Genetic, immunological, and clinical features of patients with bacterial and fungal infections due to inherited IL-17RA deficiency

“…The cell-surface expression of dysfunctional receptors is the second genetic form of AR IL-17RA deficiency to be described. The detection of surface IL-17RA should not, therefore, exclude a diagnosis of IL-17RA deficiency, as previously shown for other cytokine receptors, such as IFN-γR1 (66-69), IFN-γR2 (70,71), IL-12Rβ1 (72,73), and IL-10RA (74,75). IL-17RA deficiency has recently been reported in two siblings from Sri Lanka (60).…”

IL-10 in Humans: Lessons from the Gut, IL-10/IL-10 Receptor Deficiencies, and IL-10 Polymorphisms

“…Consequently, patients' PBMCs secreted increased amounts of TNF-α and other proinflammatory cytokines after costimulation of with IL-10 and LPS (Glocker et al 2009;Begue et al 2011;Kotlarz et al 2012;Mao et al 2012;Moran et al 2013;Engelhardt et al 2013). Furthermore, in IL-10RA-mutated B cells, IL-10-induced induction of SOCS3 was reduced (Mao et al 2012). Thus, immune cells lacking a functional IL-10 receptor were unresponsive to the negative feedback regulation provided by IL-10, leading to hyperinflammatory immune responses in the intestine.…”

“…Glocker et al were first to describe three distinct homozygous mutations in four patients with early onset enterocolitis (Glocker et al 2009). Subsequently, more mutations in the IL-10 receptor were found by different groups (Begue et al 2011;Kotlarz et al 2012;Mao et al 2012;Moran et al 2013;Engelhardt et al 2013). In addition to homozygous nonsense and missense mutations, compound heterozygous mutations (Kotlarz et al 2012;Mao et al 2012;Engelhardt et al 2013) and a splice site mutations (Moran et al 2013) were reported.…”

“…As a monogenetic model for the above-described pathophysiology, severe very early-onset forms of IBD have recently been shown to be caused by mutations in interleukin-10 (IL-10) and IL-10 receptor subunits (Glocker et al 2010(Glocker et al , 2009Begue et al 2011;Kotlarz et al 2012;Mao et al 2012;Moran et al 2013;Engelhardt et al 2013). …”

A Mendelian predisposition to B-cell lymphoma caused by IL-10R deficiency

“…Taking into account all reported patients with IL-10 (n 5 5), IL-10R1 (n 5 11), or IL-10R2 (n 5 19) deficiencies, [6][7][8][9][10]43 the frequency of developing lymphoma is estimated to be 36% (5 of 14) at the age of 7 years (in the absence of a previous HSCT). It is noteworthy that lymphomagenesis has not been reported in mice with impaired IL-10-mediated pathways, despite the onset of IBD, 11,44 suggesting either the existence of marked differences between mice and humans or insufficient follow-up of the mice in an adequate environment.…”