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Gene Review

NLRP3  -  NLR family, pyrin domain containing 3

Homo sapiens

Synonyms: AGTAVPRL, AII, AVP, Angiotensin/vasopressin receptor AII/AVP-like, C1orf7, ...
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Disease relevance of NLRP3

  • Familial cold autoinflammatory syndrome (FCAS, MIM 120100), commonly known as familial cold urticaria (FCU), is an autosomal-dominant systemic inflammatory disease characterized by intermittent episodes of rash, arthralgia, fever and conjunctivitis after generalized exposure to cold [1].
  • These include chronic infantile neurologic cutaneous and articular (CINCA) syndrome (also known as neonatal-onset multisystem inflammatory disease [NOMID]), Muckle-Wells syndrome (MWS), and familial cold urticaria (FCU) [2].
  • Because of the severe cartilage overgrowth observed in some patients with CINCA syndrome and the implications of polymorphonuclear cell infiltration in the cutaneous and neurological manifestations of this syndrome, the tissue-specific expression of CIAS1 was evaluated [3].
  • TNFRSF1A-associated periodic syndrome (TRAPS), Muckle-Wells syndrome (MWS) and renal amyloidosis [4].
  • This is the first genetic study indicating an association between the CIAS1 gene and susceptibility to essential hypertension (EH) [5].
  • We showed that osteoblasts express ASC, an adaptor molecule for NLRP3, and that these molecules associate after Salmonella infection [6].

Psychiatry related information on NLRP3


High impact information on NLRP3

  • Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome [1].
  • Muckle-Wells syndrome (MWS; MIM 191900), which also maps to chromosome 1q44, is an autosomal-dominant periodic fever syndrome with a similar phenotype except that symptoms are not precipitated by cold exposure and that sensorineural hearing loss is frequently also present [1].
  • To identify the genes for FCAS and MWS, we screened exons in the 1q44 region for mutations by direct sequencing of genomic DNA from affected individuals and controls [1].
  • The NALP3 protein is homologous to NALP1, which is a component of the inflammasome, a molecular platform that activates the proinflammatory caspases-1 and -5 [8].
  • An additional key function of Nod-like receptors is in inflammatory conditions, which has been emphasized by the identification of several different mutations in the genes encoding Nod1, Nod2 and NALP3 that are associated with susceptibility to inflammatory disorders [9].

Biological context of NLRP3

  • This gene, called CIAS1, is expressed in peripheral blood leukocytes and encodes a protein with a pyrin domain, a nucleotide-binding site (NBS, NACHT subfamily) domain and a leucine-rich repeat (LRR) motif region, suggesting a role in the regulation of inflammation and apoptosis [1].
  • Mutations in CIAS1 were only found in approximately 50% of the cases identified clinically as NOMID/CINCA syndrome, which raises the possibility of genetic heterogeneity [10].
  • We report that TNF-alpha and ligands recognized by multiple Toll-like receptors rapidly induce CIAS1 gene expression in primary human monocytes [11].
  • CONCLUSION: Our data increase the total number of known germline mutations in CIAS1 to 20, causing a spectrum of diseases ranging from familial cold autoinflammatory syndrome to Muckle-Wells syndrome to NOMID/CINCA syndrome [10].
  • Transfection of full-length CIAS1 or either of two shorter, naturally occurring isoforms dramatically inhibited TNF-alpha-induced activation of NF-kappaB reporter activity [11].

Anatomical context of NLRP3

  • In contrast, macrophages differentiated in vitro expressed relatively high cryopyrin levels, which were further induced by TNFalpha, but not by interleukin 1beta [12].
  • RESULTS: Cryopyrin mRNA was raised in RA synovium and detected in both lining and sublining regions [12].
  • Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes [3].
  • A novel CIAS1 mutation and plasma/cerebrospinal fluid cytokine profile in a German patient with neonatal-onset multisystem inflammatory disease responsive to methotrexate therapy [13].
  • Through PyD:PyD interactions, pyrin and cryopyrin, as well as several related, but still uncharacterized PyD containing proteins, appear to modulate the activity of all three of these processes, each of which plays a crucial role in the inflammatory pathways that characterize the innate immune system [14].

Associations of NLRP3 with chemical compounds


Physical interactions of NLRP3

  • In the absence of stimuli, wild-type cryopyrin was unable to bind to ASC, whereas the three mutants coimmunoprecipitated with ASC, suggesting a mechanism involved in the constitutive activation of mutant proteins [19].

Regulatory relationships of NLRP3

  • FLS from RA and OA tissue expressed low baseline levels of cryopyrin transcripts that were induced by tumour necrosis factor alpha (TNFalpha) [12].
  • These results provide evidence for a cryopyrin signaling pathway activated through the induced proximity of ASC, which is negatively regulated by pyrin [20].
  • These findings indicate that PYPAF family members participate in inflammatory signaling by regulating the activation of NF-kappa B and cytokine processing [21].

Other interactions of NLRP3

  • IL-1 regulation by CIAS1 suggests that IL-1 receptor blockade may constitute a rational approach to the treatment of NOMID/CINCA syndrome [10].
  • Expression and regulation of cryopyrin and related proteins in rheumatoid arthritis synovium [12].
  • This signaling was mimicked by oligomerization of ASC, suggesting that cryopyrin activates downstream targets as reported for other Nod family members [20].
  • Detailed analysis and new functional data regarding a number of the CATERPILLAR proteins will be described, including CIITA, cryopyrin and Monarch 1 [22].
  • TNFRSF1A-associated periodic syndrome (TRAPS) and Muckle-Wells syndrome (MWS) are two rare autosomal-dominant inherited periodic fever syndromes found in various populations [4].

Analytical, diagnostic and therapeutic context of NLRP3


  1. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Hoffman, H.M., Mueller, J.L., Broide, D.H., Wanderer, A.A., Kolodner, R.D. Nat. Genet. (2001) [Pubmed]
  2. Molecular basis of the spectral expression of CIAS1 mutations associated with phagocytic cell-mediated autoinflammatory disorders CINCA/NOMID, MWS, and FCU. Neven, B., Callebaut, I., Prieur, A.M., Feldmann, J., Bodemer, C., Lepore, L., Derfalvi, B., Benjaponpitak, S., Vesely, R., Sauvain, M.J., Oertle, S., Allen, R., Morgan, G., Borkhardt, A., Hill, C., Gardner-Medwin, J., Fischer, A., de Saint Basile, G. Blood (2004) [Pubmed]
  3. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Feldmann, J., Prieur, A.M., Quartier, P., Berquin, P., Certain, S., Cortis, E., Teillac-Hamel, D., Fischer, A., de Saint Basile, G. Am. J. Hum. Genet. (2002) [Pubmed]
  4. TNFRSF1A-associated periodic syndrome (TRAPS), Muckle-Wells syndrome (MWS) and renal amyloidosis. Dodé, C., Cuisset, L., Delpech, M., Grateau, G. J. Nephrol. (2003) [Pubmed]
  5. An intronic variable number of tandem repeat polymorphisms of the cold-induced autoinflammatory syndrome 1 (CIAS1) gene modifies gene expression and is associated with essential hypertension. Omi, T., Kumada, M., Kamesaki, T., Okuda, H., Munkhtulga, L., Yanagisawa, Y., Utsumi, N., Gotoh, T., Hata, A., Soma, M., Umemura, S., Ogihara, T., Takahashi, N., Tabara, Y., Shimada, K., Mano, H., Kajii, E., Miki, T., Iwamoto, S. Eur. J. Hum. Genet. (2006) [Pubmed]
  6. Osteoblasts express NLRP3, a nucleotide-binding domain and leucine-rich repeat region containing receptor implicated in bacterially induced cell death. McCall, S.H., Sahraei, M., Young, A.B., Worley, C.S., Duncan, J.A., Ting, J.P., Marriott, I. J. Bone Miner. Res. (2008) [Pubmed]
  7. Genitourinary anomalies in Mowat-Wilson syndrome with deletion/mutation in the zinc finger homeo box 1B gene (ZFHX1B). Report of three Italian cases with hypospadias and review. Garavelli, L., Cerruti-Mainardi, P., Virdis, R., Pedori, S., Pastore, G., Godi, M., Provera, S., Rauch, A., Zweier, C., Zollino, M., Banchini, G., Longo, N., Mowat, D., Neri, G., Bernasconi, S. Horm. Res. (2005) [Pubmed]
  8. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Agostini, L., Martinon, F., Burns, K., McDermott, M.F., Hawkins, P.N., Tschopp, J. Immunity (2004) [Pubmed]
  9. Nod-like proteins in immunity, inflammation and disease. Fritz, J.H., Ferrero, R.L., Philpott, D.J., Girardin, S.E. Nat. Immunol. (2006) [Pubmed]
  10. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Aksentijevich, I., Nowak, M., Mallah, M., Chae, J.J., Watford, W.T., Hofmann, S.R., Stein, L., Russo, R., Goldsmith, D., Dent, P., Rosenberg, H.F., Austin, F., Remmers, E.F., Balow, J.E., Rosenzweig, S., Komarow, H., Shoham, N.G., Wood, G., Jones, J., Mangra, N., Carrero, H., Adams, B.S., Moore, T.L., Schikler, K., Hoffman, H., Lovell, D.J., Lipnick, R., Barron, K., O'Shea, J.J., Kastner, D.L., Goldbach-Mansky, R. Arthritis Rheum. (2002) [Pubmed]
  11. Cutting edge: CIAS1/cryopyrin/PYPAF1/NALP3/CATERPILLER 1.1 is an inducible inflammatory mediator with NF-kappa B suppressive properties. O'Connor, W., Harton, J.A., Zhu, X., Linhoff, M.W., Ting, J.P. J. Immunol. (2003) [Pubmed]
  12. Expression and regulation of cryopyrin and related proteins in rheumatoid arthritis synovium. Rosengren, S., Hoffman, H.M., Bugbee, W., Boyle, D.L. Ann. Rheum. Dis. (2005) [Pubmed]
  13. A novel CIAS1 mutation and plasma/cerebrospinal fluid cytokine profile in a German patient with neonatal-onset multisystem inflammatory disease responsive to methotrexate therapy. Stojanov, S., Weiss, M., Lohse, P., Belohradsky, B.H. Pediatrics (2004) [Pubmed]
  14. Fire and ICE: the role of pyrin domain-containing proteins in inflammation and apoptosis. Gumucio, D.L., Diaz, A., Schaner, P., Richards, N., Babcock, C., Schaller, M., Cesena, T. Clinical and experimental rheumatology. (2002) [Pubmed]
  15. Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome. Martinon, F., Agostini, L., Meylan, E., Tschopp, J. Curr. Biol. (2004) [Pubmed]
  16. The T348M mutated form of cryopyrin is associated with defective lipopolysaccharide-induced interleukin 10 production in CINCA syndrome. Bihl, T., Vassina, E., Boettger, M.K., Goldbach-Mansky, R., Seitz, M., Villiger, P.M., Simon, H.U. Ann. Rheum. Dis. (2005) [Pubmed]
  17. Wrist muscle activation patterns and stiffness associated with stable and unstable mechanical loads. De Serres, S.J., Milner, T.E. Experimental brain research. Experimentelle Hirnforschung. Expérimentation cérébrale. (1991) [Pubmed]
  18. Disease-associated CIAS1 mutations induce monocyte death, revealing low-level mosaicism in mutation-negative cryopyrin-associated periodic syndrome patients. Saito, M., Nishikomori, R., Kambe, N., Fujisawa, A., Tanizaki, H., Takeichi, K., Imagawa, T., Iehara, T., Takada, H., Matsubayashi, T., Tanaka, H., Kawashima, H., Kawakami, K., Kagami, S., Okafuji, I., Yoshioka, T., Adachi, S., Heike, T., Miyachi, Y., Nakahata, T. Blood (2008) [Pubmed]
  19. Cryopyrin-induced interleukin 1beta secretion in monocytic cells: enhanced activity of disease-associated mutants and requirement for ASC. Dowds, T.A., Masumoto, J., Zhu, L., Inohara, N., Núñez, G. J. Biol. Chem. (2004) [Pubmed]
  20. Regulation of cryopyrin/Pypaf1 signaling by pyrin, the familial Mediterranean fever gene product. Dowds, T.A., Masumoto, J., Chen, F.F., Ogura, Y., Inohara, N., Núñez, G. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  21. PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-kappa B and caspase-1-dependent cytokine processing. Wang, L., Manji, G.A., Grenier, J.M., Al-Garawi, A., Merriam, S., Lora, J.M., Geddes, B.J., Briskin, M., DiStefano, P.S., Bertin, J. J. Biol. Chem. (2002) [Pubmed]
  22. Genomic mining of new genes and pathways in innate and adaptive immunity. Ting, J. Novartis Found. Symp. (2005) [Pubmed]
  23. Fas-associated factor 1 is a negative regulator of PYRIN-containing Apaf-1-like protein 1. Kinoshita, T., Kondoh, C., Hasegawa, M., Imamura, R., Suda, T. Int. Immunol. (2006) [Pubmed]
  24. Noninvasive tests for diagnosis of Chlamydia trachomatis infection: application of ligase chain reaction to first-catch urine specimens of women. Schachter, J., Moncada, J., Whidden, R., Shaw, H., Bolan, G., Burczak, J.D., Lee, H.H. J. Infect. Dis. (1995) [Pubmed]
  25. Central visual fields for short wavelength sensitive pathways in glaucoma and ocular hypertension. Heron, G., Adams, A.J., Husted, R. Invest. Ophthalmol. Vis. Sci. (1988) [Pubmed]
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