Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation.
AlZahrani, Mofareh S
American Association for the Advancement of Science (AAAS)
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Cuchet-Lourenço, D., Eletto, D., Wu, C., Plagnol, V., Papapietro, O., Curtis, J., Ceron-Gutierrez, L., et al. (2018). Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation.. Science, 361 (6404), 810-813. https://doi.org/10.1126/science.aar2641
RIPK1 (receptor-interacting serine/threonine kinase 1) is a master regulator of signaling pathways leading to inflammation and cell death and is of medical interest as a drug target. We report four patients from three unrelated families with complete RIPK1 deficiency caused by rare homozygous mutations. The patients suffered from recurrent infections, early-onset inflammatory bowel disease, and progressive polyarthritis. They had immunodeficiency with lymphopenia and altered production of various cytokines revealed by whole-blood assays. In vitro, RIPK1-deficient cells showed impaired mitogen-activated protein kinase activation and cytokine secretion and were prone to necroptosis. Hematopoietic stem cell transplantation reversed cytokine production defects and resolved clinical symptoms in one patient. Thus, RIPK1 plays a critical role in the human immune system.
Fibroblasts, Humans, Arthritis, Inflammatory Bowel Diseases, Lymphopenia, Severe Combined Immunodeficiency, Mitogen-Activated Protein Kinases, Cytokines, Pedigree, Alleles, Female, Male, Receptor-Interacting Protein Serine-Threonine Kinases
Medical Research Council (MR/M012328/1)
Wellcome Trust (095198/Z/10/Z)
European Research Council (260477)
External DOI: https://doi.org/10.1126/science.aar2641
This record's URL: https://www.repository.cam.ac.uk/handle/1810/279895