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Journal of Clinical Immunology
Published in: Journal of Clinical Immunology 1/2022

Open Access 01-01-2022 | Anakinra | Original Article

An Atypical Autoinflammatory Disease Due to an LRR Domain NLRP3 Mutation Enhancing Binding to NEK7

Authors: Emily A. Caseley, Samuel Lara-Reyna, James A. Poulter, Joanne Topping, Clive Carter, Fatima Nadat, Gavin P. Spickett, Sinisa Savic, Michael F. McDermott

Published in: Journal of Clinical Immunology | Issue 1/2022

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Abstract

The NLRP3 inflammasome is a vital mediator of innate immune responses. There are numerous NLRP3 mutations that cause NLRP3-associated autoinflammatory diseases (NLRP3-AIDs), mostly in or around the NACHT domain. Here, we present a patient with a rare leucine-rich repeat (LRR) domain mutation, p.Arg920Gln (p.R920Q), associated with an atypical NLRP3-AID with recurrent episodes of sore throat and extensive oropharyngeal ulceration. Unlike previously reported patients, who responded well to anakinra, her oral ulcers did not significantly improve until the PDE4 inhibitor, apremilast, was added to her treatment regimen. Here, we show that this mutation enhances interactions between NLRP3 and its endogenous inhibitor, NIMA-related kinase 7 (NEK7), by affecting charge complementarity between the two proteins. We also demonstrate that additional inflammatory mediators, including the NF-кB and IL-17 signalling pathways and IL-8 chemokine, are upregulated in the patient’s macrophages and may be directly involved in disease pathogenesis. These results highlight the role of the NLRP3 LRR domain in NLRP3-AIDs and demonstrate that the p.R920Q mutation can cause diverse phenotypes between families.
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Metadata
Title
An Atypical Autoinflammatory Disease Due to an LRR Domain NLRP3 Mutation Enhancing Binding to NEK7
Authors
Emily A. Caseley
Samuel Lara-Reyna
James A. Poulter
Joanne Topping
Clive Carter
Fatima Nadat
Gavin P. Spickett
Sinisa Savic
Michael F. McDermott
Publication date
01-01-2022
Publisher
Springer US
Published in
Journal of Clinical Immunology / Issue 1/2022
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI
https://doi.org/10.1007/s10875-021-01161-w

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