In Vitro Analysis of the Functional Effects of an NLRP3 G809S Variant with the Co-existence of MEFV Haplotype Variants in Atypical Autoinflammatory Syndrome

Overview

Journal J Clin Immunol

Publisher Springer

Specialty Allergy & Immunology

Date 2012 Sep 28

PMID 23015306

Citations 5

Authors

Kazuo Kubota

Hidenori Ohnishi

Takahide Teramoto

Eiko Matsui

Kana Murase

Hiroyuki Kanoh

Zenichiro Kato

Hideo Kaneko

Mariko Seishima

Naomi Kondo

Affiliations

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Abstract

Purpose: Hereditary periodic fever syndromes have been considered monogenic diseases. However, some recent reports have described patients with co-existence of recurrent fever responsible genes. This study assessed whether a rare variant, found in Japanese children showing atypical autoinflammatory syndrome, located in the leucine-rich repeat domain of Nod-like receptor family, pyrin domain containing 3 (NLRP3) with co-existence of Mediterranean fever (MEFV) haplotype variants may contribute to a proinflammatory phenotype using a systematic approach.

Methods: Cytokine production in serum or from peripheral blood monocytes was measured by ELISA. DNA sequence analysis of genes including NLRP3, MEFV, mevalonate kinase (MVK), and tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A) were performed on patient samples. In vitro functional assays determined the effects of the NLRP3 variants and pyrin using NF-κB activation and speck formation assays.

Results: A heterozygous genetic variant of NLRP3, G809S, was found in samples from both patients. Additionally the previously reported heterozygous MEFV variants (P369S-R408Q or E148Q-P369S-R408Q) were also detected in both patients. Serum IL-1ra and sTNFR1 levels increased in the attack phase of the disease in both patients. The production levels of IL-1β from monocytes isolated from both cases were elevated following LPS and IFN-γ stimulation. The NLRP3 G809S variant demonstrated no increase of NF-κB activity following monosodium urate stimulation, whereas it significantly increased speck formation by interacting with apoptosis-associated speck-like protein with caspase recruitment domain.

Conclusions: The phenotype of atypical autoinflammatory disease in patients could be modified by a synergistic effect with two other variants of autoinflammatory-associated genes.

Citing Articles

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Computational Modeling of NLRP3 Identifies Enhanced ATP Binding and Multimerization in Cryopyrin-Associated Periodic Syndromes.

Samson J, Ravindran Menon D, Vaddi P, Kalani Williams N, Domenico J, Zhai Z Front Immunol. 2020; 11:584364.

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Evidence of digenic inheritance in autoinflammation-associated genes.

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Genetic profiling of autoinflammatory disorders in patients with periodic fever: a prospective study.

De Pieri C, Vuch J, De Martino E, Bianco A, Ronfani L, Athanasakis E Pediatr Rheumatol Online J. 2015; 13:11.

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Clinical and genetic characterization of Japanese sporadic cases of periodic Fever, aphthous stomatitis, pharyngitis and adenitis syndrome from a single medical center in Japan.

Kubota K, Ohnishi H, Teramoto T, Kawamoto N, Kasahara K, Ohara O J Clin Immunol. 2014; 34(5):584-93.

PMID: 24760114 DOI: 10.1007/s10875-014-0043-2.

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