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Biallelic RIPK1 mutations in humans cause severe immunodeficiency, arthritis, and intestinal inflammation
23 auth. Delphine Cuchet-Lourenço, Davide Eletto, Changxing Wu, V. Plagnol, Olivier Papapietro, J. Curtis, L. Ceron-Gutierrez, C. Bacon, S. Hackett, B. Alsaleem, ...
Humans as models of human disease Mice are a convenient model for exploring the functions of cellular signaling pathways. Occasionally, however, an “experiment of nature” highlights the perils of overreliance on mice. RIPK1 is a well studied protein…
Humans as models of human disease Mice are a convenient model for exploring the functions of cellular signaling pathways. Occasionally, however, an “experiment of nature” highlights the perils of overreliance on mice. RIPK1 is a well studied protein kinase that regulates cell death. Mice deficient in RIPK1 die soon after birth because of the protein's widespread role in multiple tissues and organs. Cuchet-Lourenço et al. studied patients with inherited immunodeficiency of unknown cause (see the Perspective by Pasparakis and Kelliher). They identified inactivating mutations in the RIPK1 gene in four individuals. Unlike what has been seen in mice, the deleterious effects of RIPK1 loss in humans were confined to the immune system, a finding with potential therapeutic implications. Science, this issue p. 810; see also p. 756 A human genetics study underscores the important role of RIPK1, a regulator of cell death, in immune function. 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.
Published in
Science
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25
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7 | 2018 |
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