The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.
An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome
Open accessAbstract
Inflammasomes are innate immune sensors that respond to pathogen- and damage-associated signals with caspase-1 activation, interleukin (IL)-1β and IL-18 secretion, and macrophage pyroptosis. The discovery that dominant gain-of-function mutations in NLRP3 cause the cryopyrin-associated periodic syndromes (CAPS) and trigger spontaneous inflammasome activation and IL-1β oversecretion led to successful treatment with IL-1–blocking agents. Herein we report a de novo missense mutation (c.1009A>T, encoding p.Thr337Ser) affecting the nucleotide-binding domain of the inflammasome component NLRC4 that causes early-onset recurrent fever flares and macrophage activation syndrome (MAS). Functional analyses demonstrated spontaneous inflammasome formation and production of the inflammasome-dependent cytokines IL-1β and IL-18, with the latter exceeding the levels seen in CAPS. The NLRC4 mutation caused constitutive caspase-1 cleavage in cells transduced with mutant NLRC4 and increased production of IL-18 in both patient-derived and mutant NLRC4–transduced macrophages. Thus, we describe a new monoallelic inflammasome defect that expands the monogenic autoinflammatory disease spectrum to include MAS and suggests new targets for therapy.
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Cites
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Predicting Functional Effect of Human Missense Mutations Using PolyPhen‐2
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MutationTaster evaluates disease-causing potential of sequence alterations
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Inflammasomes in health and disease
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Use of Canakinumab in the Cryopyrin-Associated Periodic Syndrome
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Severe imbalance of IL-18/IL-18BP in patients with secondary hemophagocytic syndrome
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Interleukin-18, more than a Th1 cytokine
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Cited by
Inflammasomes: mechanism of assembly, regulation and signalling
Broz, P., & Dixit, V. M. (2016) · Nature Reviews Immunology · doi:10.1038/nri.2016.58 · Cited by 3,500
Inflammasomes: mechanism of action, role in disease, and therapeutics
Guo, H., Callaway, J. B., & Ting, J. P.-Y. (2015) · Nature Medicine · doi:10.1038/nm.3893 · Cited by 3,340
Pyroptotic cell death defends against intracellular pathogens
Jorgensen, I., & Miao, E. A. (2015) · Immunological Reviews · doi:10.1111/imr.12287 · Cited by 1,021
Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation
Romberg, N., Al Moussawi, K., Nelson-Williams, C., Stiegler, A. L., Loring, E., Choi, M., Overton, J., Meffre, E., Khokha, M. K., Huttner, A. J., et al. (2014) · Nature Genetics · doi:10.1038/ng.3066 · Cited by 517
A 360° view of the inflammasome: Mechanisms of activation, cell death, and diseases
Barnett, K. C., Li, S., Liang, K., & Ting, J. P.-Y. (2023) · Cell · doi:10.1016/j.cell.2023.04.025 · Cited by 458
Metadata
- Authors
- Canna, S. W., de Jesus, A. A., Gouni, S., Brooks, S. R., Marrero, B., Liu, Y., DiMattia, M. A., Zaal, K. J. M., Sanchez, G. A. M., Kim, H., Chapelle, D., Plass, N., Huang, Y., Villarino, A. V., Biancotto, A., Fleisher, T. A., Duncan, J. A., O'Shea, J. J., Benseler, S., Grom, A., Deng, Z., Laxer, R. M., & Goldbach-Mansky, R.
- Venue
- Nature Genetics
- Published
- 2014-09-14
- Volume
- 46
- Issue
- 10
- Pages
- 1140-1146
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2028368428
- Cited by
- 740
- References
- 11
- FWCI
- 22.88
- Type
- journal article
- Language
- en
- Open access
- green
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