ArticlePloS one2020
Two common disease-associated TYK2 variants impact exon splicing and TYK2 dosage.
Article in PloS one, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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30 citing papers in PubMed, 37 citations in OpenAlex.
- Dissecting pleiotropy to gain mechanistic insights into human disease.Nature reviews. Genetics · 2026Review
- Proteogenomic Discovery of Novel Open Reading Frames With HLA Immune Presentation on Human β-Cells.Diabetes · 2025Article
- Investigation of the transcriptional impact of rare germline JAK/STAT variants found in a Tyrolean alpine community.BMC genomics · 2025Article
- TYK2 :p.Pro1104Ala Variant Protects Against Autoimmunity by Modulating Immune Cell Levels.Immunology · 2025Article
- Identification of novel drug targets through integrative PWAS of brain and plasma proteins with Ulcerative Colitis GWAS.PloS one · 2025Article
- Therapeutic advances of targeting receptor tyrosine kinases in cancer.Signal transduction and targeted therapy · 2024Review
- Meta-DHGNN: method for CRS-related cytokines analysis in CAR-T therapy based on meta-learning directed heterogeneous graph neural network.Briefings in bioinformatics · 2024Article
- Association of endometriosis with Sjögren's syndrome: Genetic insights (Review).International journal of molecular medicine · 2024Review
- Article
- A Novel Homozygous Mutation Causing Complete TYK2 Deficiency, with Severe Respiratory Viral Infections, EBV-Driven Lymphoma, and Jamestown Canyon Viral Encephalitis.Journal of clinical immunology · 2023Article
- The Relationship between COVID-19 Severity in Children and Immunoregulatory Gene Polymorphism.Viruses · 2023Article
- Strategies to therapeutically modulate cytokine action.Nature reviews. Drug discovery · 2023Review
- Identifying pathogenic variants related to systemic lupus erythematosus by integrating genomic databases and a bioinformatic approach.Genomics & informatics · 2023Article
- The Role of Genetic Risk Factors in Pathogenesis of Childhood-Onset Systemic Lupus Erythematosus.Current issues in molecular biology · 2023Review
- TYK2 single-nucleotide variants associated with the severity of COVID-19 disease.Archives of virology · 2023Article
- Nature and nurture: understanding phenotypic variation in inborn errors of immunity.Frontiers in cellular and infection microbiology · 2023Review
- COVID-19 and systemic lupus erythematosus genetics: A balance between autoimmune disease risk and protection against infection.PLoS genetics · 2022Article
- The type 1 diabetes gene TYK2 regulates β-cell development and its responses to interferon-α.Nature communications · 2022Article
- Targeted Sequencing of Cytokine-Induced PI3K-Related Genes in Ulcerative Colitis, Colorectal Cancer and Colitis-Associated Cancer.International journal of molecular sciences · 2022Article
- Genome-wide association study identifies Sjögren's risk loci with functional implications in immune and glandular cells.Nature communications · 2022Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.