Alternative titles; symbols
HGNC Approved Gene Symbol: NLRP3
SNOMEDCT: 15123008, 239826001; ICD10CM: M04.2;
Cytogenetic location: 1q44 Genomic coordinates (GRCh38): 1:247,416,077-247,448,817 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q44 | CINCA syndrome | 607115 | Autosomal dominant | 3 |
| Deafness, autosomal dominant 34, with or without inflammation | 617772 | Autosomal dominant | 3 | |
| Familial cold inflammatory syndrome 1 | 120100 | Autosomal dominant | 3 | |
| Keratoendothelitis fugax hereditaria | 148200 | Autosomal dominant | 3 | |
| Muckle-Wells syndrome | 191900 | Autosomal dominant | 3 |
The NLRP3 gene encodes a pyrin-like protein expressed predominantly in peripheral blood leukocytes (Hoffman et al., 2001).
By large-scale sequencing of cDNAs from CD34 (142230)-positive hematopoietic stem cells, 5-prime RACE, and bioinformatics analysis, Mao et al. (1998) identified NLRP3, which showed similarity to the rat angiotensin/vasopressin (AII/Avp) receptors. The predicted human AII/Avp-like receptor gene encodes a 514-amino acid protein.
In a positional cloning effort to identify the gene mutated in familial cold-induced autoinflammatory syndrome (FCAS1; 120100) and Muckle-Wells syndrome (MWS; 191900), both of which map to 1q44, Hoffman et al. (2001) cloned and characterized NLRP3, which they called CIAS1. The full-length cDNA corresponds to a 9-exon gene encoding an open reading frame of 3,105 basepairs with 2 potential start codons in exon 1, with the second start codon meeting more Kozak criteria, and a stop codon at exon 9. Northern blot analysis identified a broad mRNA band of approximately 4 kb expressed at a low level in peripheral blood leukocytes; little or no expression was detectable in other tissues. Further analysis revealed extensive alternative splicing of exons 4 through 8 that resulted in mRNAs ranging from 3,315 to 4,170 bp, consistent with the Northern blot analysis. The predicted protein encoded by the first splice form of CIAS1 (exons 1-3, 5, and 7-9), called cryopyrin, consists of 920 amino acids with a size of 105.7 kD and a PI of 6.16. The protein sequence contains several distinct motifs including a pyrin domain in the amino terminus (amino acids 13 through 83), a central nucleotide-binding site (NBS; NACHT subfamily) domain in exon 3 (amino acids 217 to 533), and a C-terminal leucine-rich repeat (LRR) domain containing 7 leucine-rich repeats (amino acids 697 through 920). No nuclear localization signals were identified and no clear transmembrane regions were found. The largest protein potentially encoded by the 9 exons of CIAS1 consists of 1,034 amino acids with a size of 117.9 kD and 11 C-terminal leucine-rich repeats. Hoffman et al. (2001) suggested that cryopyrin is a signaling protein involved in the regulation of apoptosis.
Cryoelectron Microscopy
Sharif et al. (2019) reported a cryoelectron microscopy structure of inactive human NLRP3 in complex with NEK7 (606848) at a resolution of 3.8 angstroms. The earring-shaped NLRP3 consists of curved leucine-rich repeat and globular NACHT domains, and the C-terminal lobe of NEK7 nestles against both NLRP3 domains. Structural recognition between NLRP3 and NEK7 was confirmed by mutagenesis both in vitro and in cells. Modeling of an active NLRP3-NEK7 conformation based on the NLRC4 (606831) inflammasome predicted an additional contact between an NLRP3-bound NEK7 and a neighboring NLRP3. Mutations to this interface abolished the ability of NEK7 or NLRP3 to rescue NLRP3 activation in NEK7-knockout or NLRP3-knockout cells. Sharif et al. (2019) concluded that their data suggested that NEK7 bridges adjacent NLRP3 subunits with bipartite interactions to mediate the activation of the NLRP3 inflammasome.
By radiation hybrid analysis, Mao et al. (1998) mapped the NLRP3 gene to chromosome 1q43-q44. Using a positional cloning approach, Hoffman et al. (2001) localized the NLRP3 gene between markers D1S423 and D1S2682 on 1q44. Using rare crossover events in 4 large North American FCAS1 families, Hoffman et al. (2003) narrowed the mapping of the NLRP3 gene to a 4-cM region. They identified an unusually large 40-cM shared haplotype in 3 of the 4 families.
Agostini et al. (2004) noted that NALP1 (606636), unlike other short NALP proteins, contains a C-terminal CARD domain that interacts with and activates CASP5 (602665). CASP1 (147678) and CASP5 are activated when they assemble with NALP1 and ASC (PYCARD; 606838) to form the inflammasome, which is responsible for processing the inactive IL1B (147720) precursor (proIL1B) to release active IL1B cytokine. Using immunoprecipitation analysis, Agostini et al. (2004) found that CARD8 (609051), which contains C-terminal FIIND (function to find) and CARD domains, associated with constructs of NALP2 (609364) and NALP3 lacking the N-terminal pyrin domain and/or the C-terminal leucine-rich repeat domain. They determined that the interaction was mediated by the FIIND domain of CARD8 and the centrally located NACHT domain of NALP2 and NALP3. The pyrin domain of NALP2 and NALP3, like that of NALP1, interacted with the pyrin domain of ASC, which recruits CASP1. Transfection experiments showed that an inflammasome could be assembled containing ASC, CARD8, CASP1, and a short NALP, resulting in activation of CASP1, but not CASP5, and strong processing of proIL1B. Agostini et al. (2004) found that monocytes from patients with MWS and FCAS1 with the arg260-to-trp (R260W; 606416.0005) mutation in the NACHT domain of NALP3 displayed spontaneous processing and secretion of IL1B, suggesting the mutation resulted in an enhanced propensity for inflammasome assembly or blockage of a putative inhibitor of inflammasome assembly. Indeed, the authors found that treatment of MWS patients with the IL1B antagonist IL1RA (IL1RN; 147679) led to a rapid cessation of inflammatory symptoms.
Martinon et al. (2006) showed that monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD), both crystals found in gout, engage the CASP1-activating NALP3 inflammasome, resulting in the production of active interleukin (IL1)-1-beta (IL1B) and IL18 (600953). Macrophages from mice deficient in various components of the inflammasome such as CASP1, ASC, and NALP3 are defective in crystal-induced IL1B activation. Moreover, an impaired neutrophil influx was found in an in vivo model of crystal-induced peritonitis in inflammasome-deficient mice or mice deficient in the IL1B receptor (IL1R; 147810). Martinon et al. (2006) concluded that their findings provide insight into the molecular processes underlying the inflammatory conditions of gout and pseudogout, and further support a pivotal role of the inflammasome in several autoinflammatory diseases.
Kanneganti et al. (2006) showed the effect of cryopyrin deficiency on inflammasome function and immune responses. Cryopyrin and ASC are essential for CASP1 activation and IL1B and IL18 production in response to bacterial RNA and the imidazoquinoline compounds R837 and R848. In contrast, secretion of tumor necrosis factor-alpha (TNFA; 191160) and IL6 (147620), as well as activation of NF-kappa-B (see 164011) and mitogen-activated protein kinases (see 176948) were unaffected by cryopyrin deficiency. Furthermore, Kanneganti et al. (2006) showed that Toll-like receptors and cryopyrin control the secretion of IL1B and IL18 through different intracellular pathways. Kanneganti et al. (2006) concluded that these results reveal a critical role for cryopyrin in host defense through bacterial RNA-mediated activation of CASP1, and provide insights regarding the pathogenesis of autoinflammatory syndromes.
Mariathasan et al. (2006) demonstrated that cryopyrin-deficient macrophages cannot activate CASP1 in response to Toll-like receptor agonists plus ATP, the latter activating the P2X7 receptor (602566) to decrease intracellular potassium ion levels. The release of IL1B in response to nigericin, a potassium ionophore, and maitotoxin, a potent marine toxin, was also found to be dependent on cryopyrin. In contrast to ASC-null macrophages, cells deficient in the gene encoding cryopyrin (Cias1-null) activated CASP1 and secreted normal levels of IL1B and IL18 when infected with gram-negative Salmonella typhimurium or Francisella tularensis. Macrophages exposed to gram-positive Staphylococcus aureus or Listeria monocytogenes, however, required both ASC and cryopyrin to activate CASP1 and secrete IL1B. Therefore, Mariathasan et al. (2006) concluded that cryopyrin is essential for inflammasome activation in response to signaling pathways triggered specifically by ATP, nigericin, maitotoxin, S. aureus, or L. monocytogenes.
Using a baculoviral expression system, Duncan et al. (2007) isolated full-length recombinant NALP3. The purified protein bound ATP/dATP, but not CTP, GTP, or UTP, and had ATPase activity. Mutation of the NALP3 nucleotide-binding domain reduced ATP binding, CASP1 activation, IL1B production, cell death, macromolecular complex formation, self-association, and association with ASC. Duncan et al. (2007) suggested that nucleotide binding by NALP3 is a potential antiinflammatory drug target.
Muruve et al. (2008) demonstrated that internalized adenoviral DNA induces maturation of pro-IL1B in macrophages, which is dependent on NALP3 and ASC (606838), components of the innate cytosolic molecular complex termed the inflammasome. Correspondingly, Nalp3- and Asc-deficient mice displayed reduced innate inflammatory responses to adenovirus particles. Inflammasome activation also occurred as a result of transfected cytosolic bacterial, viral, and mammalian (host) DNA, but sensing was dependent on Asc and not Nalp3. The DNA-sensing proinflammatory pathway functions independently of TLRs and interferon regulatory factors. Thus, Muruve et al. (2008) concluded that, in addition to viral and bacterial components or danger signals in general, inflammasomes sense potentially dangerous cytoplasmic DNA, strengthening their central role in innate immunity.
Dostert et al. (2008) demonstrated that asbestos and silica are sensed by the Nalp3 inflammasome, whose subsequent activation leads to IL1B secretion. Inflammation activation is triggered by reactive oxygen species, which are generated by the NADPH oxidase upon particle phagocytosis. In a model of asbestos inhalation, Nalp3-null mice showed diminished recruitment of inflammatory cells to the lungs, paralleled by lower cytokine production. Dostert et al. (2008) concluded that their results implicated the Nalp3 inflammasome in particulate matter-related pulmonary diseases and supported its role as a major proinflammatory danger receptor.
Eisenbarth et al. (2008) showed that aluminum adjuvants activated the Nalp3 inflammasome and that production of IL1B and IL18 by macrophages in response to aluminum in vitro required intact inflammasome signaling. In Nalp3-deficient mice, Asc or Casp1 failed to mount a significant antibody response to an antigen administered with aluminum adjuvants, whereas the response to complete Freund adjuvant remained intact. Eisenbarth et al. (2008) concluded that the Nalp3 inflammasome is a crucial element in the adjuvant effect of aluminum adjuvants and that the innate inflammasome pathway can direct a humoral adaptive immune response.
Guarda et al. (2009) incubated mouse splenocyte naive, memory, and regulatory T-cell subsets with bone marrow-derived macrophages and stimulated them with anti-Cd3 (see 186740), followed by lipopolysaccharide activation and ATP stimulation. They found that inflammasome-mediated Casp1 activation and secretion of mature Il1b was blocked in the presence of memory Cd4 (186940)-positive T cells, but not other T-cell subsets. Subsequent investigation showed that multiple activators of Nalp1 and Nalp3, but not Nlrc4 (606831), were inhibited in inflammasome function by memory or in vitro-activated Cd4-positive T cells. Suppression of Nalp3 inflammasome function required cell-to-cell contact. Effector Cd4-positive T cells also decreased neutrophil recruitment in an Nalp3-dependent peritonitis mouse model. Guarda et al. (2009) concluded that effector and memory CD4-positive T cells selectively inhibit NALP1 and NALP3 inflammasomes.
Gross et al. (2009) demonstrated that the tyrosine kinase Syk (600085), operating downstream of several immunoreceptor tyrosine-based activation motif (ITAM)-coupled fungal pattern recognition receptors, controls both pro-IL1-beta (147720) synthesis and inflammasome activation after cell stimulation with Candida albicans. Whereas Syk signaling for pro-IL1-beta synthesis selectively uses the Card9 (607212) pathway, inflammasome activation by the fungus involves reactive oxygen species production and potassium efflux. Genetic deletion or pharmacologic inhibition of Syk selectively abrogated inflammasome activation by C. albicans but not by inflammasome activators such as Salmonella typhimurium or the bacterial toxin nigericin. Nlrp3 was identified as the critical NOD (see 605980)-like receptor family member that transduces the fungal recognition signal to the inflammasome adaptor Asc (PYCARD; 606838) for caspase-1 (CASP1; 147678) activation and pro-IL1-beta processing. Consistent with an essential role for Nlrp3 inflammasomes in antifungal immunity, Gross et al. (2009) showed that Nlrp3-deficient mice are hypersusceptible to C. albicans infection. Thus, Gross et al. (2009) concluded that their results demonstrated the molecular basis for IL1-beta production after fungal infection and identified a crucial function for the Nlrp3 inflammasome in mammalian host defense in vivo.
Imaeda et al. (2009) found that mice deficient in Tlr9 (605474) or the Nalp3 inflammasome components Nalp3, Casp1, or Asc, but not Ipaf (NLRC4; 606831), showed reduced mortality and liver injury in response to acetaminophen (APAP). Apoptotic hepatocytes released DNA that upregulated liver pro-Il1b and pro-Il18 in a Tlr9-dependent manner. Treatment with the antiinflammatory drug aspirin reduced sterile inflammation and liver injury by decreasing activity of the Tlr9 pathway in a Cox1 (PTGS1; 176805)- and Cox2 (PTGS2; 600262)-independent manner. Aspirin directly reduced IL1B and IL18 levels in a human monocytic cell line. Imaeda et al. (2009) concluded that there is a 2-signal requirement of TLR9 and the NALP3 inflammasome for APAP-induced injury, and they proposed that coformulation of APAP and aspirin may reduce hepatotoxicity from APAP overdose.
Using mice lacking genes involved in the NLR and TLR signaling pathways, Allen et al. (2009) demonstrated significantly increased mortality in mice lacking Pycard, Casp1 (147678), or Nlrp3, but only a moderate decrease in mice lacking Myd88 (602170), in response to influenza virus infection. Enhanced mortality was associated with reduced airway inflammation and proinflammatory cytokines. Activation of the NLRP3 inflammasome in response to virus or to RNA was dependent upon lysosomal maturation and reactive oxygen species production in human cells. Allen et al. (2009) concluded that the NLRP3 inflammasome is essential in host defense against influenza infection through the sensing of viral RNA.
Using a combination of laser reflection and fluorescence confocal microscopy, Duewell et al. (2010) revealed that minute cholesterol crystals are present in early diet-induced atherosclerotic lesions and that their appearance in mice coincides with the first appearance of inflammatory cells. Other crystalline substances can induce inflammation by stimulating the CASP1-activating NLRP3 inflammasome, which results in cleavage and secretion of IL1 family cytokines. Duewell et al. (2010) showed that cholesterol crystals activate the NLRP3 inflammasome in phagocytes in vitro in a process that involves phagolysosomal damage. Similarly, when injected intraperitoneally, cholesterol crystals induced acute inflammation, which is impaired in mice deficient in components of the NLRP3 inflammasome, cathepsin B (116810), cathepsin L (116880), or IL1 molecules. Moreover, when mice deficient in low-density lipoprotein receptor (LDLR; 606945) were transplanted with NLRP3-deficient, ASC (606838)-deficient, or IL1-alpha/beta (147760/147720)-deficient bone marrow and fed on a high cholesterol diet, they had markedly decreased early atherosclerosis and inflammasome-dependent IL18 (600953) levels. Minimally modified LDL can lead to cholesterol crystallization concomitant with NLRP3 inflammasome priming and activation in macrophages. Although there is the possibility that oxidized LDL activates the NLRP3 inflammasome in vivo, Duewell et al. (2010) concluded that crystalline cholesterol acts as an endogenous danger signal and that its deposition in arteries or elsewhere is an early cause rather than a late consequence of inflammation.
McDonald et al. (2010) used spinning disc confocal intravital microscopy to examine the kinetics and molecular mechanisms of neutrophil recruitment to sites of focal hepatic necrosis in vivo. ATP released from necrotic cells activated the Nlrp3 inflammasome to generate an inflammatory microenvironment that alerted circulating neutrophils to adhere within liver sinusoids. Subsequently, generation of an intravascular chemokine gradient directed neutrophil migration through healthy tissue toward foci of damage. Lastly, formyl-peptide signals released from necrotic cells guided neutrophils through nonperfused sinusoids into the injury.
Zhou et al. (2011) demonstrated that mitophagy/autophagy blockade leads to the accumulation of damaged, reactive oxygen species-generating mitochondria, and this in turn activates the NLRP3 inflammasome. Resting NLRP3 localizes the endoplasmic reticulum structures, whereas on inflammasome activation both NLRP3 and its adaptor ASC redistribute to the perinuclear space where they colocalize with endoplasmic reticulum and mitochondria organelle clusters. Notably, both ROS generation and inflammasome activation are suppressed when mitochondrial activity is dysregulated by inhibition of the voltage-dependent anion channel. Zhou et al. (2011) concluded that their data indicated that NLRP3 inflammasome senses mitochondrial dysfunction and may explain the frequent association of mitochondrial damage with inflammatory diseases.
Vandanmagsar et al. (2011) found that obese men of European descent with type II diabetes (NIDDM; 125853) who lost weight through decreased caloric intake and increased physical activity had a reduction in fat cell size and improvement of insulin sensitivity. Quantitative RT-PCR analysis of abdominal subcutaneous adipose tissue before and 1 year after weight loss showed a marked reduction in NLRP3 expression, lower IL1B expression, and no significant change in PYCARD expression. Calorie restriction in mice reduced expression of Nlrp3, Il1b, and Pycard over a 12-month period. Elimination of Nlrp3 expression in mice prevented obesity-induced Casp1 cleavage and Il1b and Il18 activation. The Nlrp3 inflammasome sensed lipotoxicity-associated increases in intracellular ceramide to induce Casp1 cleavage in macrophages and adipose tissue. Ablation of Nlrp3 in mice prevented obesity-induced inflammasome activation in fat depots and liver and enhanced insulin signaling. Nlrp3 elimination in obese mice reduced Il18 and adipose tissue Ifng (147570) expression, increased naive T-cell numbers, and reduced effector T-cell numbers in adipose tissue. Vandanmagsar et al. (2011) concluded that the NLRP3 inflammasome senses obesity-associated danger signals and contributes to obesity-induced inflammation and insulin resistance.
By stimulating peripheral blood mononuclear cells with drusen isolated from the eyes of 6 donors aged 80 to 97 years with age-related macular degeneration (AMD; see 603075), Doyle et al. (2012) detected production of IL1B and IL18. Stimulating a monocyte cell line with drusen resulted in increased amounts of activated CASP1. Bone marrow cells from Nlrp3 -/- mice produced significantly less Il1b than wildtype cells, whereas Tnf and Il6 production was unchanged. When adducted to human serum albumin, carboxyethylpyrrole (CEP), a biomarker of AMD, primed the inflammasome. C1Q (see 120550), a component of drusen, also mediated inflammasome activation, and this activation involved the phagolysosome. Mice immunized with CEP-adducted mouse serum albumin, modeling dry AMD, developed activated macrophages in the choroid and Bruch membrane and also above the retinal pigment epithelia. Laser-induced choroidal neovascularization (CNV), a mouse model of wet AMD, was increased in Nlrp3 -/- mice compared with wildtype or Il1r1 -/- mice, implicating Il18 in regulation of CNV development. Doyle et al. (2012) concluded that NLRP3 is protective against the major disease pathology of AMD and suggested that strategies aimed at delivering IL18 to the eye may be beneficial in preventing progression of CNV in the context of wet AMD.
Alu RNA accumulation due to DICER1 (606241) deficiency in retinal pigmented epithelium (RPE) is implicated in geographic atrophy, an advanced form of AMD. Using mouse and human RPE cells and mice lacking various genes, Tarallo et al. (2012) showed that a DICER1 deficit or Alu RNA exposure activated the NLRP3 inflammasome, triggering TLR-independent MYD88 signaling via IL18 in the RPE. Inhibition of inflammasome components, MYD88, or IL18 prevented RPE degeneration induced by DICER1 loss or Alu RNA exposure. Because RPE in human geographic atrophy contained elevated NLRP3, PYCARD, and IL18, Tarallo et al. (2012) suggested targeting this pathway for prevention and/or treatment of geographic atrophy.
Shenoy et al. (2012) found that guanylate-binding protein-5 (GBP5; 611467) promoted selective NLRP3 inflammasome responses to pathogenic bacteria and soluble but not crystalline inflammasome priming agents. Generation of Gbp5-null mice revealed pronounced caspase-1 and IL1-beta (147720)/IL18 cleavage defects in vitro and impaired host defense and Nlrp3-dependent inflammatory responses in vivo. Shenoy et al. (2012) concluded that GBP5 serves as a unique rheostat for NLRP3 inflammasome activation and that their research extends our understanding of the inflammasome complex beyond its core machinery.
Using mouse strains lacking genes involved in inflammasome activation, Rathinam et al. (2012) showed that endotoxin of Gram-negative bacteria interacted with Tlr4 (603030), followed by interaction of this complex with Trif (TICAM1; 607601), expression of and signaling by Ifnb (147640), and ultimately expression of Casp11 (see CASP4; 602664). Casp11 then worked together with the assembled Nlrp3 inflammasome to activate Casp1, leading to Il1b and Il18 secretion and Casp1-independent cell death. This pathway was not engaged by Gram-positive bacteria. Rathinam et al. (2012) concluded that TLRs are master regulators of inflammasome signaling, particularly during Gram-negative bacterial infection-induced septic shock.
Lee et al. (2012) showed that the murine calcium-sensing receptor (CASR; 601199) activates the NLRP3 inflammasome, mediated by increased intracellular calcium and decreased cellular cAMP. Calcium or other CASR agonists activate the NLRP3 inflammasome in the absence of exogenous ATP, whereas knockdown of CASR reduces inflammasome activation in response to known NLRP3 activators. CASR activates the NLRP3 inflammasome through phospholipase C (see 607120), which catalyzes inositol-1,4,5-trisphosphate production and thereby induces release of calcium from endoplasmic reticulum stores. The increased cytoplasmic ionized calcium promotes the assembly of inflammasome components, and intracellular calcium is required for spontaneous inflammasome activity in cells from patients with cryopyrin-associated periodic syndromes (CAPS). CASR stimulation also results in reduced intracellular cAMP, which independently activates the NLRP3 inflammasome. Cyclic AMP binds to NLRP3 directly to inhibit inflammasome assembly, and downregulation of cAMP relieves this inhibition. The binding affinity of cAMP for CAPS-associated mutant NLRP3 is substantially lower than for wildtype NLRP3, and the uncontrolled mature IL1-beta production from these patients' peripheral blood mononuclear cells is attenuated by increasing cAMP. Lee et al. (2012) concluded that, taken together, their findings indicated that ionized calcium and cAMP are 2 key molecular regulators of the NLRP3 inflammasome and have critical roles in the molecular pathogenesis of cryopyrin-associated periodic syndromes.
Lee et al. (2012) showed that the atypical (i.e., nontuberculous) mycobacterium M. abscessus (Mabc) robustly activated the NLRP3 inflammasome in human macrophages via dectin-1 (CLEC7A; 606264)/SYK (600085)-dependent signaling and the cytoplasmic scaffold protein SQSTM1 (601530). Both dectin-1 and TLR2 (603028) were required for Mabc-induced expression of IL1B, CAMP (600474), and DEFB4 (DEFB4A; 602215). Dectin-1-dependent SYK signaling, but not MYD88 signaling, led to activation of CASP1 and secretion of IL1B through a potassium efflux-dependent NLRP3/ASC inflammasome. Mabc-induced SQSTM1 expression was also critically involved in NLRP3 inflammasome activation. Lee et al. (2012) concluded that the NLRP3/ASC inflammasome is critical for antimicrobial responses and innate immunity to Mabc infection.
Mishra et al. (2013) infected mice lacking nitric oxide (NO) synthase-2 (NOS2A; 163730) with a strain of M. tuberculosis (see 607948) whose growth could be controlled exogenously. Using these mice, they found that Ifng and NO suppressed both bacterial growth in vivo and the continual production of Il1b by the Nlrp3 inflammasome, thereby inhibiting persistent neutrophil recruitment and preventing tissue damage. Mishra et al. (2013) concluded that NO has a dual role in promoting resistance to M. tuberculosis and in regulating inflammation, both of which are required for survival of this chronic infection.
Vande Walle et al. (2014) showed that rheumatoid arthritis (180300) in A20 (191163) myeloid cell-specific knockout mice (A20(myel-KO)) relies on the Nlrp3 inflammasome and Il1 receptor (IL1R; 147810) signaling. Macrophages lacking A20 have increased basal and lipopolysaccharide-induced expression levels of the inflammasome adaptor Nlrp3 and pro-Il1b (147720). As a result, A20 deficiency in macrophages significantly enhances Nlrp3 inflammasome-mediated caspase-1 (CASP1; 147678) activation, pyroptosis, and Il1B secretion by soluble and crystalline Nlrp3 stimuli. In contrast, activation of the Nlrc4 (606831) and Aim2 (604578) inflammasomes is not altered. Importantly, increased Nlrp3 inflammasome activation contributes to the pathology of rheumatoid arthritis in vivo, since deletion of Nlrp3, Casp1, and the Il1 receptor markedly protects against rheumatoid arthritis-associated inflammation and cartilage destruction in A20(myel-KO) mice. Vande Walle et al. (2014) concluded that these results revealed A20 as a novel negative regulator of NLRP3 inflammasome activation, and described A20(myel-KO) mice as the first experimental model to study the role of inflammasomes in the pathology of rheumatoid arthritis.
Alu-derived RNAs activate P2X7 (602566) and the NLRP3 inflammasome to cause cell death of the retinal epithelium in geographic atrophy, a type of age-related macular degeneration (ARMD; 603075). Fowler et al. (2014) found that nucleoside reverse transcriptase inhibitors (NRTIs) inhibit P2X7-mediated NLRP3 inflammasome activation independent of reverse transcriptase inhibition. Multiple approved and clinically relevant NRTIs prevented CASP1 activation, the effector of the NLRP3 inflammasome, induced by Alu RNA. NRTIs were efficacious in mouse models of geographic atrophy, choroidal neovascularization, graft-versus-host disease, and sterile liver inflammation. Fowler et al. (2014) concluded that NRTIs might be therapeutic for both dry and wet ARMD and that these drugs work at the level of P2X7 in these systems.
Using a yeast 2-hybrid screen, Giguere et al. (2014) identified human NLRP3 as a GPSM3 (618558)-interacting protein. The C-terminal leucine-rich repeat domain of NLRP3, especially the last leucine-rich repeat, and the leucine-rich motif of GPSM3 were critical for the interaction. The GPSM3-NLRP3 complex formed punctate structures throughout cells. GPSM3 interaction with NLRP3 inhibited IL1-beta production triggered by NLRP3-dependent inflammasome activators through posttranscriptional regulation of NLRP3. Immunoprecipitation analysis revealed that HSPA8 (600816) was also in complex with NLRP3 and GPSM3.
Arbore et al. (2016) found that the NLRP3 inflammasome assembled in human CD4-positive T cells and initiated CASP1-dependent IL1B secretion, thereby promoting IFNG production and T-helper-1 (Th1) differentiation in an autocrine fashion. NLRP3 assembly required intracellular C5 (120900) activation and stimulation of C5AR1 (113995), and this process was negatively regulated by C5AR2 (609949). Aberrant NLRP3 activity in T cells affected inflammatory responses in patients with CAPS and in mouse models of inflammation and infection. Arbore et al. (2016) concluded that NLRP3 inflammasome activity is involved in normal adaptive Th1 responses, as well as in innate immunity.
He et al. (2016) reported the identification of NEK7 (606848), a member of the family of mammalian NIMA-related kinases (NEK proteins), as an NLRP3-binding protein that acts downstream of potassium efflux to regulate NLRP3 oligomerization and activation. In the absence of NEK7, caspase-1 activation and IL1-beta release were abrogated in response to signals that activate NLRP3, but not NLRC4 or AIM2 inflammasomes. NLRP3-activating stimuli promoted the NLRP3-NEK7 interaction in a process that was dependent on potassium efflux. NLRP3 associated with the catalytic domain of NEK7, but the catalytic activity of NEK7 was shown to be dispensable for activation of the NLRP3 inflammasome. Activated macrophages formed a high-molecular-mass NLRP3-NEK7 complex, which, along with ASC (606838) oligomerization and ASC speck formation, was abrogated in the absence of NEK7. NEK7 was required for macrophages containing the cryopyrin-associated periodic fever syndromes (CAPS)-associated NLRP3(R258W) activating mutation to activate caspase-1. Mouse chimeras reconstituted with wildtype, Nek7 -/-, or Nlrp3 -/- hematopoietic cells showed that NEK7 was required for NLRP3 inflammasome activation in vivo. The authors concluded that NEK7 is an essential protein that acts downstream of potassium efflux to mediate NLRP3 inflammasome assembly and activation.
Camell et al. (2017) found that unbiased whole-transcriptomic analyses of adipose macrophages revealed that aging upregulates genes that control catecholamine degradation in an NLRP3 inflammasome-dependent manner. Deletion of NLRP3 in aging restored catecholamine-induced lipolysis by downregulating growth differentiation factor-3 (GDF3; 606522) and monoamine oxidase A (MAOA; 309850), which is known to degrade noradrenaline. Consistent with this, deletion of GDF3 in inflammasome-activated macrophages improved lipolysis by decreasing levels of MAOA and caspase-1 (CASP1; 147678). Furthermore, inhibition of MAOA reversed the age-related reduction in noradrenaline concentration in adipose tissue, and restored lipolysis with increased levels of the key lipolytic enzymes adipose triglyceride lipase (ATGL, or PNPLA2; 609059) and hormone-sensitive lipase (HSL, or LIPE; 151750). Camell et al. (2017) concluded that targeting neuroimmunometabolic signaling between the sympathetic nervous system and macrophages may offer novel approaches to mitigate chronic inflammation-induced metabolic impairment and functional decline.
Zhong et al. (2018) demonstrated that the synthesis of mitochondrial DNA (mtDNA), induced after the engagement of Toll-like receptors, is crucial for NLRP3 signaling. Toll-like receptors signal via the MYD88 (602170) and TRIF (607601) adaptors to trigger IRF1 (147575)-dependent transcription of CMPK2 (611787), a rate-limiting enzyme that supplies deoxyribonucleotides for mtDNA synthesis. CMPK2-dependent mtDNA synthesis is necessary for the production of oxidized mtDNA fragments after exposure to NLRP3 activators. Cytosolic oxidized mtDNA associates with the NLRP3 inflammasome complex and is required for its activation.
Chen and Chen (2018) showed that different NLRP3 stimuli lead to disassembly of the trans-Golgi network (TGN). NLRP3 is recruited to the dispersed TGN (dTGN) through ionic bonding between its conserved polybasic region and negatively charged phosphatidylinositol-4-phosphate (PtdIns4P) on the dTGN. The dTGN then serves as a scaffold for NLRP3 aggregation into multiple puncta, leading to polymerization of the adaptor protein ASC, thereby activating the downstream signaling cascade. Disruption of the interaction between NLRP3 and PtdIns4P on the dTGN blocked NLRP3 aggregation and downstream signaling. Chen and Chen (2018) concluded that recruitment of NLRP3 to the dTGN is an early and common cellular event that leads to NLRP3 aggregation and activation in response to diverse stimuli.
Using immunoprecipitation, Murakami et al. (2019) showed that Gnb1 (139380) interacted with the PYD of Nlrp3 following Nlrp3 activation in mouse bone marrow-derived macrophages. Through its interaction with Nlrp3, Gnb1 negatively regulated Nlrp3 inflammasome activation by suppressing Asc oligomerization induced by Nlrp3.
Using mice and mouse and human cells, Chen et al. (2019) showed that secretion of galectin-3 (LGALS3; 153619), including serum galectin-3, relied on activation of the NLRP3 inflammasome. The exosome pathway did not mediate NLRP3 inflammasome-driven galectin-3 secretion. Instead, gasdermin D (GSDMD; 617042) perforated the plasma membrane to allow nonexosomal release of galectin-3. Knockout analysis in mice demonstrated that galectin-3 was an Nlrp3 inflammasome effector that desensitized insulin signaling. Nlrp3 inflammasome-mediated galectin-3 secretion exacerbated insulin resistance in mice.
Samir et al. (2019) showed that the induction of stress granules specifically inhibits NLRP3 inflammasome activation, ASC (606838) speck formation, and pyroptosis. The stress granule protein DDX3X (300160) interacts with NLRP3 to drive inflammasome activation. Assembly of stress granules leads to the sequestration of DDX3X, and thereby the inhibition of NLRP3 inflammasome activation. Stress granules and the NLRP3 inflammasome compete for DDX3X molecules to coordinate the activation of innate responses and subsequent cell-fate decisions under stress conditions. Induction of stress granules or loss of DDX3X in the myeloid compartment leads to a decrease in the production of inflammasome-dependent cytokines in vivo. The findings of Samir et al. (2019) suggested that macrophages use the availability of DDX3X to interpret stress signals and choose between prosurvival stress granules and pyroptotic ASC specks. The authors concluded that their data demonstrated the role of DDX3X in driving NLRP3 inflammasome and stress granule assembly, and suggested a rheostat-like mechanistic paradigm for regulating live-or-die cell fate decisions under stress conditions.
Magupalli et al. (2020) showed that NLRP3- and pyrin (MEFV; 608107)-mediated inflammasome assembly, caspase (see 147678) activation, and IL1-beta conversion occurred at the microtubule-organizing center (MTOC) in mouse and human cells. HDAC6 (300272) was required for microtubule transport and assembly of these inflammasomes both in vitro and in mice. The authors noted that because HDAC6 can transport ubiquitinated pathologic aggregates to the MTOC for aggresome formation and autophagosomal degradation, its role in NLRP3 and pyrin inflammasome activation also provides an inherent mechanism for downregulation of these inflammasomes by autophagy.
Orecchioni et al. (2022) showed that mouse vascular macrophages express the Olfr2 olfactory receptor, the ortholog of human OR6A2 (608495), which detects octanal and activates the NLRP3 inflammasome that induces IL1B (147720) secretion. Human OR6A2 mRNA was increased in monocyte-derived macrophages and protein was detected in human aorta, where it colocalized with the macrophage marker CD68 (153634). Peroxidation of oleic acid in plasma by mouse aorta generated octanal at concentrations sufficient to activate Olfr2, and octanal supplementation exacerbated atherosclerosis in susceptible mouse models. Homozygous Ldlr (606945) knockout mice developed atherosclerosis on a high-cholesterol diet, but Ldlr/Olfr2 double-knockout mice developed aortic lesions about half the size of those with Ldlr knockout alone. The authors suggested that inhibition of OR6A2 may provide a strategy in the treatment and prevention of arteriosclerosis.
Inherited Inflammatory Disorders
Hoffman et al. (2001) identified 4 different missense mutations in exon 3 of the CIAS1 gene in 3 families with familial cold-induced inflammatory syndrome-1 (FCAS1; 120200) and in 1 family with Muckle-Wells syndrome (MWS; 191900).
Dode et al. (2002) identified CIAS1 mutations, all located in exon 3, in 9 unrelated families with MWS and in 3 unrelated families with FCAS1, also known as familial cold urticaria (FCU), originating from France, England, and Algeria. Five mutations were novel.
The R260W mutation (606416.0005) was identified in 2 families with MWS and in 2 families with FCAS1, of different ethnic origins, thereby demonstrating that a single CIAS1 mutation may cause both syndromes. This result indicated that modifier genes are involved in determining either an MWS or an FCAS1 phenotype. The finding of the G569R mutation (606416.0006) in asymptomatic individuals further emphasized the importance of a modifier gene (or genes) in determining disease phenotype. The authors suggested that identification of modifiers was likely to have significant therapeutic implications for these severe diseases.
Feldmann et al. (2002) identified heterozygous missense mutations in the CIAS1 gene (e.g., 606416.0007) in the affected members of each of 7 families with CINCA syndrome (CINCA; 607115). Because of the severe cartilage overgrowth observed in some patients with CINCA syndrome and the implications of polymorphonuclear cell infiltration in the cutaneous and neurologic manifestations of this syndrome, the tissue-specific expression of CIAS1 was evaluated. A high level of expression of CIAS1 was found to be restricted to polymorphonuclear cells and chondrocytes.
In 6 of 13 patients with CINCA syndrome, Aksentijevich et al. (2002) identified mutations in the CIAS1 gene; all were heterozygous missense substitutions in exon 3. In the 4 mutation-positive cases in which parental DNA was available, both parents were found to be negative for the substitution, suggesting that the mutations in these cases arose de novo. One patient had an asp303-to-asn mutation (606416.0008), which had previously been found in a patient with MWS and a patient with CINCA syndrome.
In 4 large North American families with FCAS1, Hoffman et al. (2003) identified a leu353-to-pro mutation in exon 3 of the CIAS1 gene (L353P; 606416.0010). As all previously reported mutations of CIAS1 occurred in exon 3, this finding added further evidence that the central NBS domain is crucial to cryopyrin function. Hoffman et al. (2003) noted that functional mutations are also seen in the NBS domain of related proteins, such as NOD2 (605956) in Blau syndrome (186580).
In 13 unrelated patients with CINCA syndrome, Neven et al. (2004) identified 7 novel mutations in the CIAS1 gene. They identified mutation hotspots in CIAS1 on the basis of all mutations described to that time and also provided evidence of genotype/phenotype correlations. The 3 conditions associated with mutation in the CIAS1 gene--FCU, MWS, and CINCA--are inherited as dominant disorders. Almost 50 independent mutations of the CIAS1 gene, including those identified by Neven et al. (2004), had been characterized. All of the mutations were missense mutations affecting exon 3 and causing a wide spectrum of disease expression. These findings strongly suggested that the mutated protein exerts a dominant-negative or a gain-of-function effect over the wildtype product and that the null mutation of 1 allele would probably have no effect or would lead to a different phenotypic expression because of haploinsufficiency.
In affected members of 2 unrelated families from North America with autosomal dominant deafness-34 (DFNA34; 617772), Nakanishi et al. (2017) identified a heterozygous missense mutation in the NLRP3 gene (R918Q; 606416.0011). The mutation, which was found by linkage analysis followed by candidate gene sequencing, segregated with the disorder in both families. Haplotype analysis suggested a founder effect for the 2 families. Laboratory studies of affected individuals showed increased IL1B (147720) secretion in response to LPS stimulation and variably increased serologic markers of inflammation compared to controls, suggesting a gain-of-function effect. Patients also showed pathologic enhancement of the cochlea on imaging, suggesting cochlear autoinflammation. Family LMG113 did not show significant additional features of an inflammatory disorder, but affected members from family LMG446 did show such features, including periodic fevers, urticaria, lymphadenopathy, conjunctivitis, ulcers, and arthralgias. The findings broadened the phenotype associated with NLRP3 mutations. Nakanishi et al. (2017) found expression of Nlrp3, Pycard, Casp1, and Il1b in mouse cochlea, and demonstrated that Nlrp3 was specifically expressed in macrophage-like cells in the cochlea. Stimulation with LPS resulted in increased IL1B secretion in cochlear tissue, indicating that innate activation of the Nlrp3 inflammasome can occur specifically in the cochlea and theoretically result in local cochlear damage and hearing loss.
Keratoendotheliitis Fugax Hereditaria
In 34 Finnish patients from 11 families with keratoendotheliitis fugax hereditaria (KEFH; 148200), Turunen et al. (2018) identified heterozygosity for a missense mutation in the NLRP3 gene (D21H; 606416.0012) that segregated with disease in the 3 families tested.
Associations With Variation in the NLRP3 Gene
Villani et al. (2009) used a candidate gene approach to identify a set of SNPs located in a predicted regulatory region on chromosome 1q44 downstream of NLRP3 that are associated with Crohn disease. The associations were consistently replicated in 4 sample sets from individuals of European descent. In the combined analysis of all samples (710 father-mother-child trios, 239 cases, and 107 controls), these SNPs were strongly associated with risk of Crohn disease (P combined = 3.49 x 10(-9), odds ratio = 1.78, confidence interval = 1.47-2.16 for rs10733113). In addition, Villani et al. (2009) observed significant associations between SNPs in the associated regions and NLRP3 expression and IL1-beta (IL1B; 147720) production. Since mutations in NLRP3 are responsible for 3 rare autoinflammatory disorders, these results suggested that the NLRP3 region is also implicated in the susceptibility of more common inflammatory diseases such as Crohn disease. In 2 independent samples of healthy donors, Villani et al. (2009) also demonstrated that the risk allele of rs6672995 (G) was associated with a decrease in lipopolysaccharide-induced IL1-beta production, and the risk allele of rs4353135 (T) was associated with a decrease in baseline NLRP3 expression. All 3 SNPs in the associated 5.3-kb region influenced NLRP3 at both the gene expression and functional levels.
Eklund et al. (2014) used Mycobacterium tuberculosis (see 607948) to infect macrophages of individuals who had inflammatory disease and associated polymorphisms in NLRP3 (met299 to val (M299V) or gln705 to lys (Q705K)) or in both NLRP3 and CARD8 (cys10 to ter (C10X)). In individuals with combined NLRP3 and CARD8 variants, the authors observed restricted bacterial growth in cells. The variants, in combination, led to constitutive secretion of IL1B, elevated IL1B levels after infection, and enhanced CD63 (155740)-positive phagolysosomal fusion. Restricted growth was also observed in healthy blood donors who had variants in both genes (Q705K in NLRP3 and C10X in CARD8), but not in those carrying only 1 of the variants. Eklund et al. (2014) concluded that gain-of-function variants in NLRP3 (i.e., M299V or Q705K) in combination with the C10X variant in CARD8 result in superior control of M. tuberculosis growth.
By analyzing the immune responses of mice carrying an R258W mutation in the Nlrp3 gene, which is equivalent to the R260W mutation (606416.0005) associated with Muckle-Wells syndrome and familial cold autoinflammatory syndrome, Meng et al. (2009) found that antigen-presenting cells from mutant mice produced massive amounts of Il1b upon stimulation with microbial components in the absence of ATP, most likely due to a diminished inflammasome activation threshold allowing a response to a small amount of agonist. The mutant mice exhibited skin inflammation characterized by neutrophil infiltration and an Il1b-dependent Th17 (603149) dominant cytokine response. Meng et al. (2009) concluded that the R258W mutation mimics human Muckle-Wells syndrome and leads to inflammasome hyperactivation and Th17 cell-dominant immunopathology.
Thomas et al. (2009) found that mice lacking Casp1 (147678) or Nlrp3 exhibited significantly increased morbidity in response to influenza virus infection. Enhanced morbidity correlated with reduced neutrophil and monocyte recruitment and reduced production of cytokines, notably Il1 and Il18, and chemokines, including Mip2 (CXCL2; 139110) and Kc (CXCL1; 155730). However, adaptive response and virus control were not impaired in mutant mice. Early epithelial necrosis was more severe in infected mutant mice, with extensive collagen deposition leading to later respiratory compromise, suggesting a function for the cryopyrin inflammasome in healing responses. Thomas et al. (2009) concluded that NLRP3 and CASP1 are central to both innate immunity and to moderating lung pathology in influenza pneumonia.
Using a mouse model of mucosal Candida albicans infection, Hise et al. (2009) showed that Tlr2 (603028) and dectin-1 (CLEC7A; 606264) controlled Il1b transcription, whereas Nlrp3, Asc, and Casp1 regulated processing of pro-Il1b into the active, mature 17-kD protein. Tlr2, dectin-1, and the Nlrp3 inflammasome were essential for defense against disseminated infection and mortality in vivo. Mice lacking Il1r had increased fungal burden in tongue. Hise et al. (2009) concluded that the NLRP3 inflammasome and IL1B production have essential roles in the regulation of mucosal antifungal host defense.
The propensity of helminths, such as schistosomes (see 181460), to immunomodulate the host's immune system is an essential aspect of their survival. Ritter et al. (2010) stimulated mouse bone marrow-derived dendritic cells (BMDCs) with soluble schistosomal egg antigens (SEAs) after prestimulation with different TLR ligands and observed suppressed secretion of Tnf and Il6 and increased Nlrp3-dependent Il1b production. Induction of Il1b was phagocytosis-independent, but it required production of reactive oxygen species, potassium efflux, and functional Syk signaling, suggesting inflammasome activation. SEA stimulation of BMDCs lacking Fcrg (see 146740) or dectin-2 (CLEC6A; 613579) resulted in significantly reduced Il1b production compared with wildtype BMDCs, suggesting that SEA triggers dectin-2, which couples with Fcrg to activate the Syk kinase signaling pathway that controls Nlrp3 inflammasome activation and Il1b release. Infection of mice lacking Nlrp3 or Asc with S. mansoni resulted in no difference in parasite burden, but decreased liver pathology and downregulated Th1, Th2, and Th17 adaptive immune responses. Ritter et al. (2010) concluded that SEA components induce IL1B production and that NLRP3 plays a crucial role during S. mansoni infection.
Heneka et al. (2013) found that Nlrp3-null or Casp1-null mice carrying mutations associated with familial Alzheimer disease (104300) were largely protected from loss of spatial memory and other sequelae associated with Alzheimer disease, and demonstrated reduced brain caspase-1 and interleukin-1-beta activation as well as enhanced amyloid-beta (see APP, 104760) clearance. Furthermore, NLRP3 inflammasome deficiency skewed microglial cells to an M2 phenotype and resulted in the decreased deposition of amyloid-beta in the APP/PS1 (104311) model of Alzheimer disease. Heneka et al. (2013) concluded that their results showed an important role for the NLRP3/caspase-1 axis in the pathogenesis of Alzheimer disease.
Chenery et al. (2019) found that Nlrp3 -/- mice displayed elevated recruitment of early innate immune cells to lung during Nippostrongylus infection, leading to protective innate immune responses in lung, as well as enhanced type-2 effector response in intestine. Elevated early innate immune cell recruitment impacted resolution of inflammation and resulted in lung damage. Lung damage was caused by a failure of Nlrp3 -/- mice to repair it following N. brasiliensis infection due to dysregulated type-2 immunity and repair responses. Nlrp3 deficiency also elevated expression of Il4 (147780) and Ym1 in lung during infection with N. brasiliensis, leading to enhanced macrophage responsiveness to Il4r-alpha (IL4R; 147781) signaling in Nlrp3 -/- mice. Although Nrlrp3 is most commonly associated with forming an inflammasome, lung antihelminth responses regulated by Nlrp3 were inflammasome-independent during N. brasiliensis infection in mice.
Bats, the only flying mammals, are a reservoir species for various RNA viruses, including coronaviruses. Using confocal microscopy, flow cytometry, and immunoblot analysis, Ahn et al. (2019) showed both in cells and in vivo that bats tolerated high viral loads due to a dampened inflammatory response, specifically through reduced Nlrp3 activation. In contrast, mouse and human NLRP3 inflammasome activation occurred in response to the same viral stimuli. Genomic analysis revealed an exon 7-skipping splice variant in bats, but not other mammals, that contributed to dampened Nlrp3 activation in bats. Ahn et al. (2019) concluded that bats exhibit enhanced immune tolerance rather than enhanced antiviral defense and proposed that dampened inflammasome activation may also be associated with bat longevity.
Using mouse models, Ising et al. (2019) showed that loss of Nlrp3 inflammasome function reduced tau (MAPT; 157140) hyperphosphorylation and aggregation by regulating tau kinases and phosphatases. Tau activated the Nlrp3 inflammasome, and intracerebral injection of fibrillar amyloid-beta-containing brain homogenates induced tau pathology in an Nlrp3-dependent manner. Ising et al. (2019) concluded that NLRP3 inflammasome activation plays an important role in tauopathy pathogenesis. Their findings supported the amyloid cascade hypothesis in Alzheimer disease, demonstrating that neurofibrillary tangles develop downstream of amyloid-beta-induced microglia activation.
Li et al. (2020) generated pigs homozygous for a gain-of-function arg259-to-trp (R25W) mutation in Nlrp3, corresponding to the human R260W mutation linked to CAPS. Some mutant pigs were stillborn, and all live-born piglets were weak at birth and suffered from tremor and hind-leg weakness. Some live-born pigs died within a week, and some displayed symptoms similar to those of human newborns with CAPS. Short-lived pigs suffered from systemic inflammation, as the R259W mutation significantly increased expression of Nlrp3, caspase-1, and inflammation-associated cytokines and factors. Inflammation led to multiorgan failure with myocardial fibrosis and death of mutant pigs. About half of the live-born mutant pigs grew to adulthood with no morphologic abnormalities, and some even gave birth to offspring, but the mutants gained significantly less weight and exhibited stronger inflammation compared with wildtype. The authors also generated pigs heterozygous for R259W by naturally mating males homozygous for R259W with wildtype females. All heterozygous pigs were born alive and most survived, but some of were weak at birth and died within 2 days. Heterozygous pigs displayed symptoms similar to those of their homozygous mutant parents, but the severity and probability of occurrence were reduced. The surviving heterozygous pigs showed normal weight gain.
In a 4-generation family with familial cold autoinflammatory syndrome (FCAS1; 120100) previously reported by Shepard (1971), Hoffman et al. (2001) identified a C-to-T transition at nucleotide 1316 in exon 3 of the CIAS1 gene, resulting in an alanine-to-valine substitution at codon 439 (A439V).
In a family with familial cold autoinflammatory syndrome (FCAS1; 120100) previously reported by Vlagopoulos et al. (1975), Hoffman et al. (2001) identified a G-to-A transition at nucleotide 592 in exon 3 of the CIAS1 gene, resulting in a valine-to-methionine substitution at codon 198 (V198M).
In a family with familial cold autoinflammatory syndrome (FCAS1; 120100), previously reported by Wanderer (1979), Hoffman et al. (2001) identified an A-to-G transition at nucleotide 1880 in exon 3 of the CIAS1 gene, resulting in a glutamic acid-to-glycine substitution at codon 627 (E627G).
In a family with Muckle-Wells syndrome (MWS; 191900), Hoffman et al. (2001) identified a C-to-T transition at nucleotide 1055 in exon 3 of the CIAS1 gene, resulting in an alanine-to-valine substitution at codon 352 (A352V).
In 2 families with Muckle-Wells syndrome (MWS; 191900) and 2 families with familial cold autoinflammatory syndrome (FCAS1; 120100) of different ethnic origins, Dode et al. (2002) found the cause of the disorder to be a heterozygous arg260-to-trp (R260W) mutation in the CIAS1 gene. The development of progressive sensorineural deafness and renal amyloidosis are features that distinguish MWS from FCAS.
Dode et al. (2002) described an English family in which only 1 member was affected with Muckle-Wells syndrome (MWS; 191900) caused by a gly569-to-arg (G569R) mutation in the CIAS1 gene. The mother had the same mutation but was asymptomatic.
In a patient with CINCA syndrome (CINCA; 607115), Feldmann et al. (2002) identified a T-to-C transition at nucleotide 1718 in the CIAS1 gene, resulting in a phe573-to-ser (F573S) substitution. The disorder in this patient had neonatal onset, skin lesions, chronic meningitis, joint inflammation, sensory organ impairment, and dysmorphism.
CINCA Syndrome
Feldmann et al. (2002) identified a G-to-A transition at nucleotide 907 in the CIAS1 gene, leading to an asp303-to-asn (D303N) substitution, in a girl with CINCA syndrome (CINCA; 607115). The patient had neonatal onset, skin lesions, chronic meningitis, joint inflammation, and sensory organ impairment. A photograph of the patient at the age of 12 years showed characteristic frontal bossing and protruding eyes. Her father was also affected.
Mukle-Wells Syndrome
Dode et al. (2002) identified the D303N mutation in a patient who presented with all the clinical criteria of Muckle-Wells syndrome (MWS; 191900). The mutation was apparently de novo in this patient.
In a patient with CINCA syndrome (CINCA; 607115), Feldmann et al. (2002) identified a T-to-C transition at nucleotide 926 in the CIAS1 gene, leading to a phe309-to-ser (F309S) substitution. The features of the disorder in this patient were neonatal onset, skin lesions, chronic meningitis, joint inflammation, radiologically severe arthropathy, sensory organ impairment, and dysmorphism. Radiologic changes at the age of 2.5 years included bilateral severe bony deformities of the knees, resulting in hard bony enlargement without any suggestion of synovial thickening on palpation. Growth cartilage 'burst' and irregular opacification of the patella were illustrated.
In 4 large North American families with familial cold autoinflammatory syndrome (FCAS1; 120100), Hoffman et al. (2003) identified a heterozygous 1058T-C transition in exon 3 of the CIAS1 gene, causing a leu353-to-pro (L353P) mutation. They determined that 3 of these families shared an unusually large 40-cM haplotype.
In affected members of 2 unrelated families from North America (families LMG113 and LMG446) with autosomal dominant deafness-34 with or without inflammation (DFNA34; 617772), Nakanishi et al. (2017) identified a heterozygous c.2753G-A transition (c.2753G-A, NM_001243133.1) in exon 7 of the NLRP3 gene, resulting in an arg918-to-gln (R918Q) substitution at a conserved residue in the LRR domain. The mutation, which was found by linkage analysis followed by candidate gene sequencing in family LMG113, segregated with the disorder in both families. It was not found in the ExAC database (January 19, 2017) or in 572 control chromosomes. Haplotype analysis suggested a founder effect for the 2 families. Laboratory studies of affected individuals showed increased IL1B (147720) secretion in response to LPS stimulation and variably increased serologic markers of inflammation compared to controls, suggesting a gain-of-function effect. Direct functional studies of the variant were not performed. Patients also showed pathologic enhancement of the cochlea on imaging, suggesting cochlear autoinflammation. Family LMG113 did not show significant additional features of an inflammatory disorder, but affected members from family LMG446 did show such features, including periodic fevers, urticaria, lymphadenopathy, conjunctivitis, ulcers, and arthralgias. The findings broadened the phenotype associated with NLRP3 mutations.
In affected individuals from 7 Finnish families with keratoendotheliitis fugax hereditaria (KEFH; 148200), including the family originally reported by Ruusuvaara and Setala (1987), as well as 4 sporadic Finnish patients, Turunen et al. (2018) identified heterozygosity for a c.61G-C transversion (c.61G-C, NM_004895.4) in exon 1 of the NLRP3 gene, resulting in an asp21-to-his (D21H) substitution at a highly conserved residue. The mutation was not found in 7 unaffected members from 3 families who were tested. In September 2017, the mutation was present in the SISu database at a minor allele frequency (MAF) of 0.023%, and in the ExAC database at an MAF of 0.0090% in the aggregated non-Finnish European populations; it was not present in any other ExAC populations.
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