IRAK1 Gene

Last updated on: 23.06.2022

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Definition
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The IRAK1 gene (IRAK1 stands for "Interleukin 1 Receptor Associated Kinase 1") is a protein-coding gene that is loaclized on chromosome Xq28. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. The IRAK1 gene encodes interleukin-1 receptor-associated kinase 1, one of two putative serine/threonine kinases that associate with the interleukin-1 receptor (IL1R) upon stimulation. The IRAK1 gene is partially responsible for IL1-induced upregulation of the transcription factor NF-kappa B.

Clinical picture
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Diseases associated with IRAK1 include:

  • Lupus Erythematosus in both childhood and adulthood (see references below - Jacob CO et al 2009).
  • and
  • X-linked MECP2 defect syndrome due to large de novo Xq28 chromosomal deletion including MECP2 and IRAK1.
  • Furthermore, mutations in IRAK1 (rs1059703 T allele) are associated with increased severity of rheumatoid arthritis (Hosseini N et al. 2021).

Note(s)
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The IRAKs (interleukin-1 receptor-associated kinases) are serine-threonine kinases, EC 2.7.11.1, which are essential regulators of IL-1R- and TLR-mediated signal transduction. To date, four IRAK isoforms have been identified: IRAK1, IRAK2, IRAK3 (IRAK-M), and IRAK4.

Inhibitors of IRAK1 show cytotoxic activity at single-digit micromolar concentrations in a group of WM, DLBCL, and lymphoma cell lines expressing MYD88.

Lupus erythematosus: In the study of approximately 5,000 subjects and healthy controls, 5 SNPs in the IRAK1 gene showed disease association in both adult and childhood SLE in 4 different ethnic groups, with a 4-SNP haplotype (GGGG) strongly associated with disease. The finding of a gene on the X chromosome as a disease susceptibility factor in human SLE suggests that the sex difference in SLE may be due in part to genes on the sex chromosome (Jacob CO et al 2009).

Literature
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  1. Hatcher JM et al (2020) Discovery of a Selective, Covalent IRAK1 Inhibitor with Antiproliferative Activity in MYD88 Mutated B-Cell Lymphoma. ACS Med Chem Lett 11:2238-2243
  2. Hosseini N et al (2021) IRAK1 gene polymorphism in rheumatoid arthritis. Immunol Invest 50:304-321.
  3. Jacob CO et al (2009) Identification of IRAK1 as a risk gene with critical role in the pathogenesis of systemic lupus erythematosus. Proc Natl Acad Sci U S A 106: 6256-6261.

Last updated on: 23.06.2022