|Coordinate||59,565,974 bp (GRCm38)|
|Base Change||T ⇒ G (forward strand)|
|Gene Name||NLR family, pyrin domain containing 3|
|Synonym(s)||Cias1, cryopyrin, Pypaf1, NALP3, Mmig1|
|Chromosomal Location||59,541,568-59,566,955 bp (+)|
|MGI Phenotype||Strain: 3686871
Mice homozygous for null mutations exhibit attenuated inflammatory responses related to decrease secretion of IL-1beta and IL-18. Mice heterozygous for activating mutations suffer from autoinflammatory attacks that lead to organ failure and death before weaning.
|Amino Acid Change||Cysteine changed to Tryptophan|
|Institutional Source||Beutler Lab|
C987W in Ensembl: ENSMUSP00000078440 (fasta)
|Gene Model||not available|
|Predicted Effect||probably benign
PolyPhen 2 Score 0.334 (Sensitivity: 0.90; Specificity: 0.89)
|Phenotypic Category||immune system, NALP3 inflammasome signaling defect|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Semidominant|
|Local Stock||Sperm, gDNA|
|Last Updated||03/02/2017 12:19 PM by Katherine Timer|
|Record Created||11/10/2009 12:00 AM|
The ND1 phenotype was initially identified among G3 mice homozygous for mutations induced by N-ethyl-N-nitrosourea (ENU) and tested in the NALP3 Inflammasome Screen (D3891, D3892 and D3893; Figure 1). Peritoneal macrophages isolated from both ND1 homozygous and heterozygous mice secreted reduced amounts of the proinflammatory cytokine interleukin (IL)-1β in response to priming with lipopolysaccharide (LPS) followed by nigericin treatment (Figure 1), with heterozygotes producing IL-1β at a level intermediate between that produced by wild type and homozygous macrophages. ND1 mice produced normal levels of tumor necrosis factor (TNF)-α in response to LPS stimulation alone, suggesting that signaling from the Toll-like receptor 4 (TLR4), which senses LPS, was unimpaired.
|Nature of Mutation|
The Nlrp3 gene was directly sequenced as a candidate gene and a T to G transversion was found at position 3187 of the Nlrp3 transcript in exon 9 of 10 total exons using Genbank record NM_145827. The mutation is located in the eighth coding exon.
The mutated nucleotide is indicated in red lettering, and causes a cysteine to tryptophan substitution at residue 987 of the NLRP3 protein.
The Nlrp3 gene encodes a 1033 amino acid protein that is a member of the nucleotide-binding and oligomerization domain (NOD)-like receptor (NLR) or CATERPILLER [for CARD, transcription enhancer, R(purine)-binding, pyrin, lots of leucine repeats] family (1). The structure of NLRs resembles that of a subset of plant disease-resistance (R) proteins that are involved in the hypersensitive response to virulent plant pathogens. Both NLRs and R proteins contain a C-terminal leucine-rich repeat (LRR) domain, a central oligomerization NACHT usually with a C-terminal extension known as the NACHT associated domain (NAD), and an N-terminal effector domain. The N-terminus of R proteins often contains a Toll/interleukin-1 receptor (TIR) domain, while NLRP3 contains a pyrin domain (PYD) at this location. Other N-terminal NLR domains include the caspase-recruitment domain (CARD) and the baculovirus inhibitor of apoptosis protein repeat (BIR) (2;3). NLRP3 (NLR family, pyrin domain containing protein 3) is also known as NALP3, PYPAF1 and cryopyrin (1;4). Human and mouse NLRP3 are highly conserved with 82.7% amino acid identity (5;6).
The NACHT domain is a 300 to 400 residue predicted nucleotide triphosphatase (NTPase) domain, which is found in animal, fungal and bacterial proteins. The name NACHT is derived from the four plant and animal proteins which initially defined the unique features of this domain: the neuronal apoptosis inhibitory protein (NAIP), MHC class II transcription activator (CIITA), incompatibility locus protein from Podospora anserina (HET-E), and telomerase-associated protein (TP1). In NLR proteins, the NACHT and NAD, also known as the NBD (nucleotide-binding domain), consists of twelve distinct conserved motifs, including the ATP/GTPase specific P-loop (Walker A motif), and the magnesium (Mg2+)-binding site (Walker B motif) (10;11). The Walker A motif contains the sequence GKS/T corresponding to amino acids 227-229 in mouse NLRP3 with the lysine coordinating the γ-phosphate of NTPs (6;12). The unique features of the NACHT domain include the prevalence of small residues (glycine, alanine or serine) directly C-terminal of the Mg2+-coordinating aspartate in the Walker B motif, in place of a second acidic residue prevalent in other NTPases. A second acidic residue is typically found in the NACHT-containing proteins two positions downstream. Distal to the Walker A and B motifs, these domains also a conserved pattern of polar, aromatic and hydrophobic residues that is not seen in any other NTPase family (10). Modeling studies of the NLRP3 NACHT domain suggests that it consists of a five-stranded β-sheet surrounded by α-helices with the Walker A, Walker B, and a sensor motif containing a conserved polar residue found at the end of the parallel strands forming the nucleotide-binding site. The NAD extension of the NLRP3 NACHT domain consists of three helical subdomains (13;14). The NACHT domain of NLRP3 specifically displays ATPase activity, and mutation of Walker A and B motifs reduces ATP binding, as well as NLRP3 protein function including caspase-1 activation, IL-1β production, cell death, macromolecular complex formation, self-association, and association with ASC (see Background). Disruption of nucleotide binding also abolishes the constitutive activation of disease-associated mutants (12). The mouse NLRP3 NBD comprises amino acids 216-532.
LRR-containing domains generally consist of 2-45 motifs of 20-30 amino acids in length, which are predicted to fold into an arc or horseshoe shape (15). LRRs occur in proteins ranging from viruses to eukaryotes, and appear to provide a structural framework for the formation of protein-protein interactions. Proteins containing LRRs include tyrosine kinase receptors, cell-adhesion molecules, virulence factors, and extracellular matrix-binding glycoproteins, and are involved in a variety of biological processes, including signal transduction, cell adhesion, DNA repair, recombination, transcription, RNA processing, disease resistance, apoptosis, and the immune response where they are suggested to bind to and sense molecules that trigger inflammation (2). Sequence analyses of LRR proteins suggests the existence of several different subfamilies of LRRs (16), but all major classes of LRRs have curved horseshoe structures with a parallel β-sheet on the concave side and mostly helical elements on the convex side. Eleven-residue segments of the LRRs (LxxLxLxxN/CxL), corresponding to the β-strand and adjacent loop regions, are conserved in LRR proteins, whereas the remaining parts of the repeats may be very different. Despite the differences, each of the variable parts contains two half-turns at both ends and a "linear" segment, usually formed by a helix, in the middle. The concave face and the adjacent loops are the most common protein interaction surfaces on LRR proteins. 3D structures of some LRR proteins-ligand complexes show that the concave surface of LRR domain is ideal for interaction with α-helical structures. Molecular modeling suggests that the conserved pattern LxxLxL, which is shorter than the previously proposed LxxLxLxxN/CxL, is sufficient to impart the characteristic horseshoe curvature to proteins with 20- to 30-residue repeats (15;17). The LRR-containing domain of NLRP3 is thought to bind to the NBD domain preventing oligomerization and protein activation (2), but has also been shown to associate with thioredoxin-interacting protein (TXNIP) (18).
It is not clear how many LRRs NLRP3 contains as anywhere from seven to twelve have been reported for mouse and human proteins (4-6;9). Both human and mouse NLRP3 undergo extensive alternative splicing of coding exons 4-9, resulting in mRNAs of varying sizes detected in peripheral blood leukocyte cDNA (5;6).
The ND1 mutation results in a cysteine to tryptophan change in coding exon 8. Depending on the prediction program used, this residue may occur in the second to last LRR, the final LRR, or falls just outside the LRR domain.
In mice, Nlrp3 mRNA is detectable using RT-PCR analysis in all tissues examined, except the thymus (19). Particularly high levels were reported in the eye and skin, as well as peripheral blood leukocytes (6;9). Nlrp3 mRNA is expressed in a variety of resting immune cells, including macrophages, dendritic cells, and neutrophils, and is seen at low levels in B cells and T cells (6;19;20). The expression of Nlrp3 mRNA was upregulated in a subset of helper T cells (Th2), while expression in macrophages is increased by LPS stimulation (19). In murine lungs infected with influenza virus, Nlrp3 mRNA is also detectable in mouse airway epithelial cells (20), and NLRP3 protein is detectable in pancreatic islet cells (18).
Unlike in mice, Northern blot analysis of human tissues found NLRP3 mRNA restricted to peripheral blood leukocytes (5). Human NLRP3 mRNA is also increased by TLR agonists (21). Both mouse and human osteoblasts express NLRP3 mRNA (22). In human immune cells, NLRP3 protein is detected in granulocytes, dendritic cells, B and T lymphocytes, and very weakly in monocytes. In other tissues, NLRP3 expression is mainly restricted to non-keratinizing epithelia in the oropharynx, esophagus, and ectodermic, and is found in the urothelial layer in the bladder. NLRP3 is predominantly cytoplasmic (23).
Certain members of the NLR family, including IPAF (ICE protease-activating factor), NLRP1b, and NLRP3, are able to oligomerize through their NBD domains and assemble into large caspase-1-activating multiprotein complexes termed inflammasomes upon the detection of pathogenic or other danger signals in the cytoplasm. Initially, NLRP3 was shown to assemble a 700kDa, caspase-1 activating complex under certain in vitro conditions (24). Caspase-1 is a cysteine protease that is present under resting conditions in an inactive precursor form with an N-terminal CARD-containing prodomain capable of mediating homotypic interactions. The CARD domain of procaspase-1 recruits the protease to the inflammasome where it undergoes autoproteolytic maturation into its active form. Activated caspase-1 is able to cleave a variety of substrates, most notably the proinflammatory cytokines IL-1β, IL-18 and IL-33 to generate biologically active proteins. In turn, these cytokines mediate a wide variety of biological effects associated with infection, inflammation, and autoimmune processes in by activating key processes such as the nuclear factor κB (NF-κB; see the record for panr2) and mitogen-activated protein kinase (MAPK) pathways The adaptor protein ASC plays an important role in inflammasome assembly by binding to the NLRP3 PYD through its own PYD, and then recruiting procaspase-1 to the complex through its CARD domain [reviewed by (25)]. Another CARD-containing adaptor protein, human CARDINAL, has been shown to be part of a reconstituted human NLRP3 inflammasome, but the functional role for this protein is unclear as no murine homolog for CARDINAL has been identified (26). The association of NLRP3 with a molecular chaperone complex consisting of HSP90 and the ubiquitin ligase–associated protein SGT may also be important for the assembly of the NLRP3 inflammasome (27).
Table 1. NLRP3 inflammasome activators
Most studies have focused on the role of NLRP3 in immune cells due to the importance of the inflammasome in the innate immune system. However, other cell types and tissues also appear to initiate inflammation by activating NLRP3, including skin keratinocytes (19;52;53), and insulin-producing pancreatic β-cells (18). Interestingly, various immune cells differentially regulate the synthesis, processing and release of IL-1β. Macrophages first require an inflammatory stimulus (TLR ligand) to induce large intracellular stores of pro-IL-1β, followed by a second stimulus, such as extracellular ATP or bacterial toxins, resulting in activation of the NLRP3 inflammasome and release of active, mature IL-1β (19;56). Monocytes, however, only require stimulation with TLR ligands since they possess a constitutively activated caspase-1 (56). Effector and memory CD4+ T cells can suppress potentially damaging inflammation caused by inflammasome activity (57).
A total of 93 disease-associated mutations have been found in humans in the NLRP3 gene according to the Infevers database, an online database for autoinflammatory mutations (58-60). These mutations cause a range of phenotypes that encompass three autoinflammatory disorders: Muckle-Wells syndrome (MWS; #191900), familial cold autoinflammatory syndrome (FCAS1; OMIM #120100), and chronic infantile neurologic cutaneous and articular syndrome (CINCA; OMIM #607115), also known as NOMID for neonatal onset multisystem inflammatory disease (5;61;62). Collectively, these diseases are known as cryopyrin associated periodic syndrome (CAPS). CINCA syndrome is a severe chronic inflammatory disease of early onset, characterized by cutaneous symptoms, central nervous system involvement, and arthropathy (62). Familial cold autoinflammatory syndrome is characterized clinically by recurrent attacks of a maculopapular rash associated with arthralgias, myalgias, fever and chills, and swelling of the extremities after exposure to cold. Muckle-Wells syndrome (MWS) is characterized by episodic skin rash, arthralgias, and fever associated with late-onset sensorineural deafness and renal amyloidosis (61). The vast majority of NLRP3 mutations causing these diseases are missense mutations, and most of them are found in the central coding exon 3 encoding the NBD and surrounding sequence with clustering occurring on one side of domain along the nucleotide-binding cleft in loops next to the parallel β-strands forming the NACHT domain (13;14). This region is predicted to be involved in intermolecular contacts. Human NLRP3 mutations result in enhanced inflammasome sensitivity and activity leading to elevated levels of IL-1β, and these diseases are often treated by IL-1β inhibitors (63;64). Recently, polymorphisms in regulatory elements that cause decreased NLRP3 expression and IL-1β production were linked with increased susceptibility to Crohn’s disease (OMIM #266600) (65).
Macrophages from Nlrp3 knockout mice display deficient responses to stimuli that normally activates the NLRP3 inflammasome, and display decreased secretion of IL-1β and IL-18 (19;29;32;37). Accordingly, NLRP3-deficient animals are more susceptible to various pathogenic organisms including influenza (20;38), adenovirus (39), and C. albicans (41;42). Mice carrying mutations corresponding to activating human NLRP3 variants have also been generated (66;67). These animals display spontaneous autoinflammatory disease, although the symptoms appear more severe than in humans, ranging from severe skin inflammation with neutrophilic infiltration associated with poor health (67) to widespread inflammation of many organs and death before weaning (66). Genetic background may contribute to disease severity. Examination of inflammasome activity in these animals showed a hypersensitive response and increased production of proinflammatory cytokines in response to NLRP3 stimuli. Most of the amino acids where human disease-causing mutations occur are conserved in the mouse (6).
None of the activating human NLRP3 mutations occur in coding exon 8 where the ND1 mutation occurs, and the ND1 mutation in mice is likely to be an inactivating rather than an activating mutation of Nlrp3. ND1 mice have not been tested in vivo for immunodeficient or autoimmune phenotypes, but macrophages from these animals are not responsive to NLRP3 activators, suggesting that the NLRP3 protein in these animals, if expressed, is inactive or has reduced activity. There are no known inactivating mutations in NLRP3 in humans, although mutations in the regulatory regions of the NLRP3 gene are associated with reduced NLRP3 expression and Crohn’s disease (65). The vast majority of the activating mutations that cause autoinflammatory disorders reside in exon 3, which encodes the NBD and surrounding sequences. These data strongly suggest that mutation of the NBD, perhaps rendering the protein permanently able to bind to and hydrolyze ATP or unable to bind to the inhibitory LRRs that prevent self-oligomerization, is the basis behind constitutive activation of the protein. Only three mutations have been identified in humans occurring outside of exon 3 that cause disease. Two of these occur in exon 4 and one occurs in exon 6. Both of these exons are predicted to encode LRRs. As the LRRs are thought to bind to the NBD and inhibit inflammasome formation, it is likely that these mutations lead to defective inhibition by the LRRs of the NBD and increased inflammasome activity.
The ND1 mutation occurs at amino acid 987 near the C-terminus of the protein. It is unclear whether this residue is located within the LRR domain or not, but may affect the function of the LRR domain. In addition to inhibiting the NBD, the LRRs of NLRP3 may be involved in sensing activating stimuli. The association of the NLRP3 LRR domain with TXNIP, resulting in inflammasome activation, supports this hypothesis (18). Thus, mutation of the LRRs could result in decreased protein activity instead of increased protein activity depending on the residues affected. The mutation of residues important for self-binding may lead to constitutive protein activation, while mutating residues that are important in binding to other molecules may lead to decreased protein function. Alternatively, mutations in these regions could disrupt the characteristic structure of the LRR repeats, indirectly affecting protein-protein interactions. The semidominant nature of the ND1 mutation is likely due to the aberrant protein product oligomerizing with wild type protein and rendering the entire inflammasome unresponsive to stimuli.
|Primers||Primers cannot be located by automatic search.|
ND1 genotyping is performed by amplifying the region containing the mutation using PCR, followed by sequencing of the amplified region to detect the single nucleotide transition.
ND1(F): 5’- ACAGCTTAAAGGCTAAGCCCCTGC -3’
ND1(R): 5’- TTCCACGCCTACCAGGAAATCTCG -3’
1) 95°C 2:00
2) 95°C 0:30
3) 56°C 0:30
4) 72°C 1:00
5) repeat steps (2-4) 29X
6) 72°C 7:00
7) 4°C 8
Primers for sequencing
ND1 _seq(F): 5'- GGTTGGCTTCGAACTCAGAAATC -3'
ND1 _seq(R): 5’- CTAAGGCACGTTTTGTTTCACG -3’
The following sequence of 921 nucleotides (NCBI Mouse Genome Build 37.1, Chromosome 11, bases 59,378,853 to 59,379,774) is amplified:
agcccctgcc accacagtcc tgccaactgc aaacattcat ttggtccatt gatactttgt
ggaaatctga ggggaacata atgtttagaa aaagtcaatt gacaaatttc tgttactatt
ttggtctgtt caacccagta ccttgggaaa agaaacttcc atctaaagag gggagaaaag
aaaccatatc atatgaagca gcttcacgct ggtcagtctg tggtttgttg ttgttgttgt
tttcaagaca gggtttatct gtgtagccct ggcttgcctg gaactcactc tgtagaccag
gttggcttcg aactcagaaa tccgcctgct tctgcctccc aagtgctggg attaaaggtg
tgcaccacca ctgcccagcc caatctgcgc tttttatgca aatgaaactg caggtttgga
gacccggaag tatggatggt caaggctatt ttctttatat cacccttctc ttctcaaaga
ttagacaact gcagcctcac ctcacacagc tgctggaatc tctccacaat tctgacccac
aaccacagcc ttcggaagct gaacctgggc aacaatgatc ttggcgatct gtgcgtggtg
accctctgtg aggtgctgaa acagcagggc tgcctcctgc agagcctaca gtgagtgtgg
tttgcctaga gcttctcatg gggtaggcga gcggggtgct gaggggaggg tgaccacggg
acaaaagtca gagtttctct ggattaattt gcagttttct gaagagtcca actcaaagct
tcttttctgt gttcacaggt tgggtgaaat gtacttaaat cgtgaaacaa aacgtgcctt
agaagcgctc caggaagaaa agcctgagct gactatagtc ttcgagattt cctggtaggc
Primer binding sites are underlined; sequencing primer binding sites are highlighted in gray; the mutated T is indicated in red.
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|Science Writers||Nora G. Smart|
|Illustrators||Diantha La Vine, Katherine Timer|
|Authors||Hua Huang, Bruce Beutler|