Journal Article

Two common disease-associated TYK2 variants impact exon splicing and TYK2 dosage

Li, Zhi, Patin, Etienne, Rotival, Maxime, Michel, Frédérique, Pellegrini, Sandra

2020

Overview

TYK2 belongs to the JAK protein tyrosine kinase family and mediates signaling of numerous antiviral and immunoregulatory cytokines (type I and type III IFNs, IL-10, IL-12, IL-22, IL-23) in immune and non-immune cells. After many years of genetic association studies, TYK2 is recognized as a susceptibility gene for some inflammatory and autoimmune diseases (AID). Seven TYK2 variants have been associated with AIDs in Europeans, and establishing their causality remains challenging. Previous work showed that a protective variant (P1104A) is hypomorphic and also a risk allele for mycobacterial infection. Here, we have studied two AID-associated common TYK2 variants: rs12720270 located in intron 7 and rs2304256, a non-synonymous variant in exon 8 that causes a valine to phenylalanine substitution (c.1084 G > T, Val362Phe). We found that this amino acid substitution does not alter TYK2 expression, catalytic activity or ability to relay signaling in EBV-B cell lines or in reconstituted TYK2-null cells. Based on in silico predictions that these variants may impact splicing of exon 8, we: i) analyzed TYK2 transcripts in genotyped EBV-B cells and in CRISPR/Cas9-edited cells, ii) measured splicing using minigene assays, and iii) performed eQTL (expression quantitative trait locus) analysis of TYK2 transcripts in primary monocytes and whole blood cells. Our results reveal that the two variants promote the inclusion of exon 8, which, we demonstrate, is essential for TYK2 binding to cognate receptors. In addition and in line with GTEx (Genetic Tissue Expression) data, our eQTL results show that rs2304256 mildly enhances TYK2 expression in whole blood. In all, these findings suggest that these TYK2 variants are not neutral but instead have a potential impact in AID.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Alleles / Amino acid substitution / Amino Acid Substitution - genetics / Amino acids / Analysis / Antiviral agents / Antiviral drugs / Autoimmune diseases / Autoimmune Diseases - blood / Autoimmune Diseases - genetics / Autoimmune Diseases - pathology / B cells / B-Lymphocytes - metabolism / B-Lymphocytes - pathology / Bacterial infections / Biology and Life Sciences / Blood / Blood cells / Catalytic activity / Cell lines / CRISPR / Cytokines / Cytokines - chemistry / Cytokines - genetics / Development and progression / Disease / Disease susceptibility / Europeans / Gene expression / Gene Expression Regulation - genetics / Gene mapping / Genetic aspects / Genetic Association Studies / Genetic Predisposition to Disease / Genetic research / Genetics / Genotype / Health aspects / Health risks / Human genetics / Humans / Immune system / Immunology / Immunoregulation / Infection / Inflammation - blood / Inflammation - genetics / Inflammation - pathology / Interleukin 10 / Interleukin 12 / Interleukin 22 / Interleukin 23 / Kinases / Life Sciences / Lymphocytes / Lymphocytes B / Medical research / Medicine and Health Sciences / Monocytes / Null cells / Phenols (Class of compounds) / Phenylalanine / Phenylalanine - genetics / Phosphorylation / Polymorphism, Single Nucleotide - genetics / Protein-tyrosine kinase / Proteins / Psoriasis / Quantitative trait loci / Quantitative Trait Loci - genetics / Receptors / Research and Analysis Methods / Signaling / Splicing / Substitutes / TYK2 Kinase - blood / TYK2 Kinase - genetics / Tyk2 protein / Tyrosine / Valine