Copy number variations and founder effect underlying complete IL-10Rβ deficiency in Portuguese kindreds

Abstract

Mutations in interleukin-10 receptor (IL-10R) genes are one cause of very early-onset inflammatory bowel disease with perianal lesions, which can be cured by hematopoietic stem cell transplantation. Using a functional test, which assesses responsiveness of peripheral monocytes to IL-10, we identified three unrelated Portuguese patients carrying two novel IL-10RB mutations. In the three patients, sequencing of genomic DNA identified the same large deletion of exon 3 which precluded protein expression. This mutation was homozygous in two patients born from consanguineous families and heterozygous in the third patient born from unrelated parents. Microsatellite analysis of the IL10RB genomic region revealed a common haplotype in the three Portuguese families pointing to a founder deletion inherited from a common ancestor 400 years ago. In the third patient, surface expression of IL-10R was normal but signaling in response to IL-10 was impaired. Complementary DNA sequencing and next-generation sequencing of IL10RB locus with custom-made probes revealed a ≈ 6 Kb duplication encompassing the exon 6 which leads to a frameshift mutation and a loss of the TYK2-interacting Box 2 motif. Altogether, we describe two novel copy number variations in IL10RB, one with founder effect and one preserving cell surface expression but abolishing signaling.

Herpes simplex encephalitis in a patient with a distinctive form of inherited IFNAR1 deficiency

“…Moreover, the viral phenotypes of patient fibroblasts were not rescued by treatment with IFN-a2b or -b, further confirming a complete IFNAR1 deficiency. Complete cytokine receptor deficiency due to the expression at the cell surface of a non-functional receptor has already been documented for IFNGR1, IFNGR2, IL17RA, IL10RA, IL10RB, IL6ST, and IL12RB1, with mutations impairing cytokine binding(56,(74)(75)(76)(77)(78)(79)(80). By contrast to these previous observations, the mutant IFNAR1 reported here is loss-of-function due to the absence of most of its intracellular domain, abolishing its signaling activity.…”

A Systematic Review of Monogenic Inflammatory Bowel Disease

“…Further variant types, such as CNVs, intronic variants, synonymous variants, and inversions, often are missed by WES, 22,23 and poor coverage of some regions of known monogenic IBD genes by WES has been well described. 14,19 It is likely that 8 cases with heterozygouslike inheritance in AR monogenic disorder had these variants (Supplementary Table 7).…”

Human genetics of life-threatening influenza pneumonitis

“…These infections are considered to be systemic because the physical barrier is breached by injection. By contrast, IL10R2 deficiency, which cripples cellular responses to IL-10, IL-22, IL-26 and type III IFNs, appears to be associated with inflammatory bowel diseases (IBDs) rather than severe infections (Glocker et al 2009;Pigneur et al 2013;Karaca et al 2016;Huang et al 2017;Charbit-Henrion et al 2018). This is because IL10R2 is shared by several IL-10 family cytokines, including IL-10, IL-22, and IL-26, in addition to IFN-λ (Shouval et al 2014;Ouyang and O'Garra 2019).…”