title: 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.
authors.affiliation: Department of Paediatrics & Adolescent Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
authors.forename: H
authors.initials: H
authors.lastname: Mao
authors.forename: W
authors.initials: W
authors.lastname: Yang
authors.forename: P P W
authors.initials: PP
authors.lastname: Lee
authors.forename: M H-K
authors.initials: MH
authors.lastname: Ho
authors.forename: J
authors.initials: J
authors.lastname: Yang
authors.forename: S
authors.initials: S
authors.lastname: Zeng
authors.forename: C-Y
authors.initials: CY
authors.lastname: Chong
authors.forename: T-L
authors.initials: TL
authors.lastname: Lee
authors.forename: W
authors.initials: W
authors.lastname: Tu
authors.forename: Y-L
authors.initials: YL
authors.lastname: Lau
mesh_terms: D019943:Amino Acid Substitution; D001483:Base Sequence; D003424:Crohn Disease / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D059472:Exome; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D016753:Interleukin-10 / Q000378:metabolism; D053709:Interleukin-10 Receptor alpha Subunit / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D015398:Signal Transduction
chemical_list: D053709:Interleukin-10 Receptor alpha Subunit; D016753:Interleukin-10