Alternative titles; symbols
HGNC Approved Gene Symbol: NLRP12
SNOMEDCT: 783146009;
Cytogenetic location: 19q13.42 Genomic coordinates (GRCh38): 19:53,793,584-53,824,403 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.42 | Familial cold autoinflammatory syndrome 2 | 611762 | Autosomal dominant | 3 |
NALPs are cytoplasmic proteins that form a subfamily within the larger CATERPILLER protein family. Most short NALPs, such as NALP12, have an N-terminal pyrin (MEFV; 608107) domain (PYD), followed by a NACHT domain, a NACHT-associated domain (NAD), and a C-terminal leucine-rich repeat (LRR) region. The long NALP, NALP1 (606636), also has a C-terminal extension containing a function to find domain (FIIND) and a caspase recruitment domain (CARD). NALPs are implicated in the activation of proinflammatory caspases (e.g., CASP1; 147678) via their involvement in multiprotein complexes called inflammasomes (Tschopp et al., 2003).
Using representational difference analysis with a nitric oxide-treated leukemia cell line, Shami et al. (2001) isolated a cDNA encoding NALP12, which they termed RNO. Northern blot analysis revealed expression of a 3.0-kb transcript in polymorphonuclear cells and monocytes.
By searching databases for PYPAF homologs, Wang et al. (2002) identified NALP12, which they called PYPAF7. The predicted 1,061-amino acid protein has an N-terminal PYRIN domain, a central NACHT-type nucleotide-binding site domain, and a C-terminal domain with at least 12 LRR motifs. Northern blot and RT-PCR analyses revealed expression in peripheral blood leukocytes, with little to no expression in 75 other tissues and cell lines examined. Real-time PCR detected expression predominantly in eosinophils and granulocytes, with lower expression in monocytes.
By searching for genes with homology to CIITA (MHC2TA; 600005), followed by RT-PCR and RACE using monocyte cell line cDNA, Williams et al. (2003) obtained a cDNA encoding NALP12, which they called monarch-1. The full-length 1,063-amino acid monarch-1 protein is identical to PYPAF7 (Wang et al., 2002) except that it has an additional arg at position 692. Williams et al. (2003) also identified monarch-1 splice variants lacking 9 (isoform II), exons 7 and 8 (isoform III), and exons 7 through 9 (isoform IV).
Using coexpression studies, Wang et al. (2002) found that PYPAF7 associated with ASC (PYCARD; 606838) in a PYD-dependent manner. Immunoblot and luciferase reporter analyses showed that ASC and PYPAF7 synergistically participated in activation of NFKB (see 164011) and procaspase-1. Wang et al. (2002) concluded that PYPAF7 has a role in the transduction of proinflammatory signals leading to activation of NFKB and procaspase-1.
By microarray and real-time RT-PCR analyses following expression of monarch-1 in nonexpressing cell lines, Williams et al. (2003) found that monarch-1 upregulated classical and nonclassical MHC I genes, as well as LMP7 (PSMB8; 177046). TNF (191160) and IFNG (147570), which upregulate MHC expression, downregulated monarch-1 expression, suggesting that monarch-1 may represent a separate pathway for MHC I induction.
By genomic sequence analysis, Wang et al. (2002) mapped the NALP12 gene to chromosome 19q13.4 in close proximity to most other NALP genes.
Ulland et al. (2016) stated that the mouse Nlrp12 gene maps to chromosome 7.
In affected members of 2 unrelated families with familial cold autoinflammatory syndrome-2 (FCAS2; 611762), Jeru et al. (2008) identified heterozygous mutations in the NLRP12 gene (609648.0001 and 609648.0002). The findings indicated a dominant mode of expression through haploinsufficiency.
In 4 affected members of an Italian family with variable manifestations of FCAS2, Borghini et al. (2011) identified a heterozygous missense mutation in the NLRP12 gene (D294E; 609648.0003).
In 2 unrelated patients with FCAS2, Jeru et al. (2011) identified a heterozygous missense mutation in the NLRP12 gene (R352C; 609648.0004).
Vitale et al. (2013) identified a heterozygous missense variant in the NLRP12 gene (F402L; 609648.0005) in 6 unrelated Italian probands with FCAS2. The variant showed a high frequency (up to 5%) in various databases, and Vitale et al. (2013) suggested that it may be a low-penetrance mutation. Shen et al. (2017) identified a heterozygous F402L mutation in 3 unrelated Han Chinese patients with adult-onset FCAS2 and no family history of the disorder.
Ulland et al. (2016) reported that C57BL/6J mice have a dominant defect in neutrophil recruitment that leads to increased susceptibility to bacterial infection compared with the C57BL/6N substrain. They identified the cause of the defect as a missense polymorphism in the C-terminal leucine-rich repeat domain of Nlrp12 in C57BL/6J mice. Nlrp12-knockout mice exhibited a similar defect in neutrophil recruitment and increased susceptibility to bacterial infections. In Nlrp12-knockout mice, absence of Nlrp12 did not impact development of neutrophils or their release from bone marrow into peripheral circulation. Instead, neutrophils were unable to exit from peripheral circulation and migrate into lung parenchyma, suggesting a defect in transendothelial migration. Macrophages of C57BL/6J and Nlrp12-knockout mice had diminished Cxcl1 (155730) production in response to a variety of pathogens. Nlrp12 was involved in controlling not only intracellular gram-negative bacteria, but also extracellular gram-negative and gram-positive pathogens. The authors concluded that NLRP12 does not participate in assembly or activation of an inflammasome in response to infection, but that macrophages require NLRP12 expression for effective recruitment of neutrophils to inflammatory sites via its control of CXCL1 production.
In a father and his twin sons with cold autoinflammatory syndrome-2 (FCAS2; 611762), Jeru et al. (2008) identified a heterozygous 850C-T transition in exon 3 of the NLRP12 gene, resulting in an arg284-to-ter (R284X) substitution within the nucleotide binding site of the protein. The family was from Guadeloupe. The phenotype included episodic fever, arthralgia, myalgia, and urticaria triggered by cold exposure. Both sons had sensorineural hearing loss. In vitro functional expression studies showed that the mutant NLRP12 had reduced inhibitory action against NF-kappa-B (164011) compared to wildtype NLRP12.
Xia et al. (2016) noted that the R284X mutation had been reported at a very low frequency in several databases, including the 1000 Genomes Project, Exome Sequencing Project, and ExAC.
In a father and daughter from Guadeloupe with cold autoinflammatory syndrome-2 (FCAS2; 611762), Jeru et al. (2008) identified a heterozygous 1-bp insertion (2072+3insT) within the donor splice site of intron 3, resulting in a frameshift and premature protein truncation. The daughter had a more severe phenotype, characterized by episodic fever, abdominal pain, buccal aphthous ulcers, and arthralgia triggered by cold. In vitro functional expression studies showed that the mutant NLRP12 had reduced inhibitory action against NF-kappa-B (164011) compared to wildtype NLRP12.
Xia et al. (2016) noted that the c.2072+3insT mutation had not been reported in the 1000 Genomes Project, Exome Sequencing Project, or ExAC databases.
In 4 affected members of an Italian family with variable manifestations of cold autoinflammatory syndrome-2 (FCAS2; 611762), Borghini et al. (2011) identified a heterozygous c.882C-G transversion in exon 3 of the NLRP12 gene, resulting in an asp294-to-glu (D294E) substitution in the highly conserved sequence Walker B, considered necessary for ATP binding. The mutation, which was found by direct sequencing of exon 3 of the NLRP12 gene in 50 patients with a similar disorder, segregated with the disorder in the family. The mutation was not found in 80 healthy Italian controls. In vitro functional expression studies in HEK293 cells showed that the D294E mutation did not result in decreased inhibitory action against NF-kappa-B (see 164011), but rather showed similar inhibitory activity as the wildtype protein. Patient-derived monocytes did not show increased quantitative secretion of IL1B (147720) compared to controls when stimulated with pathogen-associated molecular patterns (PAMPs). However, patient cells showed altered kinetics of IL1B secretion, with significant acceleration of IL1B secretion compared to controls in a given time frame. Patient cells also showed increased production of reactive oxygen species and upregulation of antioxidant systems, resulting in rapid exhaustion of the antioxidant systems compared to controls. These changes were most apparent in the more severely affected individual and less apparent in the least affected individual.
Xia et al. (2016) noted that the D294E mutations had been reported at a low frequency (8.132 x 10(-6)) in the ExAC database, but not in the 1000 Genomes Project or Exome Sequencing Project databases.
In 2 unrelated patients with cold autoinflammatory syndrome-2 (FCAS2; 611762), Jeru et al. (2011) identified a heterozygous c.1054C-T transition in exon 3 of the NLRP12 gene, resulting in an arg352-to-cys (R352C) substitution in the NBS domain. The mutation, which was found by direct sequencing of the NLRP12 gene, occurred at a CpG dinucleotide and thus could correspond to a hot spot. The patients were of Armenian and Italian descent, respectively, and the mutation was not found in over 200 ethnically matched controls. In vitro functional expression studies in HEK293 cells showed that the mutant protein did not affect the NF-kappa-B (see 164011) inhibitory activity of NLRP12. However, the R352C mutant showed enhanced ability to induce the processing of caspase-1 (CASP1; 147678) compared to wildtype, consistent with a gain-of-function effect. Transfected cells also showed significantly more speck formation compared to controls. Specks represent intracellular aggregates reflecting activation of the caspase-1/IL1B pathway. Although IL1B levels were not ascertained in these patients, the findings suggested that the R352C mutant protein leads to increased CASP1 processing, which would result in increased IL1B secretion and a hyperinflammatory state.
In 5 unrelated Italian probands with cold autoinflammatory syndrome-2 (FCAS2; 611762), Vitale et al. (2013) identified a heterozygous variant in the NLRP12 gene, resulting in a phe402-to-leu (F402L) substitution at a conserved residue in the NBD domain. The variant was not found in 72 ethnically matched controls, but Vitale et al. (2013) noted that it had been observed at frequencies of up to 5% in control databases from the general population. The authors suggested that it may be a low-penetrance mutation rather than a polymorphism. Functional studies of the variant and studies of patient cells were not performed.
In 3 unrelated Han Chinese patients with adult-onset FCAS2, Shen et al. (2017) identified a heterozygous c.1206C-G transversion in the NLRP12 gene, resulting in a phe402-to-leu (F402L) substitution. The mutations were found by whole-genome sequencing of periodic fever genes and confirmed by Sanger sequencing. Functional studies of the variant and studies of patient cells were not performed. One patient (patient 3) also carried a heterozygous missense variant (G304R) in the MEFV gene (608107), but she did not respond to treatment with methotrexate or colchicine, suggesting that the NLRP12 variant was responsible for the disorder.
Xia et al. (2016) noted that the F402L variant was present at low frequencies (less than 5.2 x 10(-2)) in the 1000 Genomes Project, Exome Sequencing Project, and ExAC databases.
In 4 members of a 4-generation Chinese family with cold autoinflammatory syndrome-2 (FCAS2; 611762), Xia et al. (2016) identified a heterozygous c.1223G-A transition in exon 3 of the NLRP12 gene, resulting in a trp408-to-ter (W408X) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was not found in the dbSNP (build 138), 1000 Genomes Project, Exome Sequencing Project, or ExAC databases, or in 1,500 in-house Chinese exomes. Structural modeling predicted that the mutation would result in a protein lacking the entire C-terminal LRR region and partial deletion of the NACHT domain, most likely leading to protein dysfunction. However, functional studies of the variant and studies of patient cells were not performed.
Borghini, S., Tassi, S., Chiesa, S., Caroli, F., Carta, S., Caorsi, R., Fiore, M., Delfino, L., Lasiglie, D., Ferraris, C., Traggiai, E., Di Duca, M., Santamaria, G., D'Osualdo, A., Tosca, M., Martini, A., Ceccherini, I., Rubartelli, A., Gattorno, M. Clinical presentation and pathogenesis of cold-induced autoinflammatory disease in a family with recurrence of an NLRP12 mutation. Arthritis Rheum. 63: 830-839, 2011. [PubMed: 21360512] [Full Text: https://doi.org/10.1002/art.30170]
Jeru, I., Duquesnoy, P., Fernandes-Alnemri, T., Cochet, E., Yu, J. W., Lackmy-Port-Lis, M., Grimprel, E., Landman-Parker, J., Hentgen, V., Marlin, S., McElreavey, K., Sarkisian, T., Grateau, F., Alnemri, E. S., Amselem, S. Mutations in NALP12 cause hereditary periodic fever syndromes. Proc. Nat. Acad. Sci. 105: 1614-1619, 2008. [PubMed: 18230725] [Full Text: https://doi.org/10.1073/pnas.0708616105]
Jeru, I., Le Borgne, G., Cochet, E., Hayrapetyan, H., Duquesnoy, P., Grateau, G., Morali, A., Sarkisian, T., Amselem, S. Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes. Arthritis Rheum. 63: 1459-1464, 2011. [PubMed: 21538323] [Full Text: https://doi.org/10.1002/art.30241]
Shami, P. J., Kanai, N., Wang, L. Y., Vreeke, T. M., Parker, C. J. Identification and characterization of a novel gene that is upregulated in leukaemia cells by nitric oxide. Brit. J. Haemat. 112: 138-147, 2001. [PubMed: 11167794] [Full Text: https://doi.org/10.1046/j.1365-2141.2001.02491.x]
Shen, M., Tang, L., Shi, X., Zeng, X., Yao, Q. NLRP12 autoinflammatory disease: a Chinese case series and literature review. Clin. Rheum. 36: 1661-1667, 2017. [PubMed: 27633793] [Full Text: https://doi.org/10.1007/s10067-016-3410-y]
Tschopp, J., Martinon, F., Burns, K. NALPs: a novel protein family involved in inflammation. Nature Rev. Molec. Cell Biol. 4: 95-104, 2003. [PubMed: 12563287] [Full Text: https://doi.org/10.1038/nrm1019]
Ulland, T. K., Jain, N., Hornick, E. E., Elliott, E. I., Clay, G. M., Sadler, J. J., Mills, K. A. M., Janowski, A. M., Volk, A. P. D., Wang, K., Legge, K. L., Gakhar, L., Bourdi, M., Ferguson, P. J., Wilson, M. E., Cassel, S. L., Sutterwala, F. S. Nlrp12 mutation causes C57BL/6J strain-specific defect in neutrophil recruitment. Nature Commun. 7: 13180, 2016. Note: Electronic Article. [PubMed: 27779193] [Full Text: https://doi.org/10.1038/ncomms13180]
Vitale, A., Rigante, D., Maggio, M. C., Emmi, G., Romano, M., Silvestri, E., Lucherini, O. M., Emmi, L., Gerloni, V., Cantarini, L. Rare NLRP12 variants associated with the NLRP12-autoinflammatory disorder phenotype: an Italian case series. Clin. Exp. Rheum. 31: 155-156, 2013. [PubMed: 24064030]
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. PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-kappa-B and caspase-1-dependent cytokine processing. J. Biol. Chem. 277: 29874-29880, 2002. [PubMed: 12019269] [Full Text: https://doi.org/10.1074/jbc.M203915200]
Williams, K. L., Taxman, D. J., Linhoff, M. W., Reed, W., Ting, J. P.-Y. Cutting edge: Monarch-1: a pyrin/nucleotide-binding domain/leucine-rich repeat protein that controls classical and nonclassical MHC class I genes. J. Immun. 170: 5354-5358, 2003. [PubMed: 12759408] [Full Text: https://doi.org/10.4049/jimmunol.170.11.5354]
Xia, X., Dai, C., Zhu, X., Liao, Q., Luo, X., Fu, Y., Wang, L. Identification of a novel NLRP12 nonsense mutation (Trp408X) in the extremely rare disease FCAS by exome sequencing. PLoS One 11: e0156981, 2016. Note: Electronic Article. [PubMed: 27314497] [Full Text: https://doi.org/10.1371/journal.pone.0156981]