Phenotypic Mutation 'nd5' (pdf version)
Allelend5
Mutation Type missense
Chromosome11
Coordinate59,456,705 bp (GRCm39)
Base Change T ⇒ C (forward strand)
Gene Nlrp3
Gene Name NLR family, pyrin domain containing 3
Synonym(s) Mmig1, Cias1, NALP3, cryopyrin, Pypaf1
Chromosomal Location 59,432,395-59,457,781 bp (+) (GRCm39)
MGI Phenotype FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes a pyrin-like protein containing a pyrin domain, a nucleotide-binding site (NBS) domain, and a leucine-rich repeat (LRR) motif. This protein interacts with the apoptosis-associated speck-like protein PYCARD/ASC, which contains a caspase recruitment domain, and is a member of the NALP3 inflammasome complex. This complex functions as an upstream activator of NF-kappaB signaling, and it plays a role in the regulation of inflammation, the immune response, and apoptosis. Mutations in this gene are associated with familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous and articular (CINCA) syndrome, and neonatal-onset multisystem inflammatory disease (NOMID). Multiple alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. Alternative 5' UTR structures are suggested by available data; however, insufficient evidence is available to determine if all of the represented 5' UTR splice patterns are biologically valid. [provided by RefSeq, Oct 2008]
PHENOTYPE: 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. [provided by MGI curators]
Accession Number

NCBI RefSeq: NM_145827; MGI: 2653833

MappedYes 
Amino Acid Change Tryptophan changed to Arginine
Institutional SourceBeutler Lab
Gene Model not available
AlphaFold Q8R4B8
SMART Domains Protein: ENSMUSP00000078440
Gene: ENSMUSG00000032691
AA Change: W956R

DomainStartEndE-ValueType
PYRIN 4 87 6.39e-33 SMART
FISNA 135 206 1.45e-22 SMART
Pfam:NACHT 216 385 6.7e-52 PFAM
low complexity region 533 539 N/A INTRINSIC
low complexity region 688 697 N/A INTRINSIC
LRR_RI 737 764 1.07e-9 SMART
LRR 766 793 5.13e1 SMART
LRR 794 821 3.86e-7 SMART
LRR 823 850 1.62e0 SMART
LRR 851 878 3.39e-3 SMART
LRR 880 907 1.2e2 SMART
LRR 908 935 2.24e-3 SMART
LRR 937 964 2.16e2 SMART
LRR 965 992 8.73e-6 SMART
Predicted Effect probably benign

PolyPhen 2 Score 0.009 (Sensitivity: 0.96; Specificity: 0.77)
(Using ENSMUST00000079476)
SMART Domains Protein: ENSMUSP00000098707
Gene: ENSMUSG00000032691
AA Change: W956R

DomainStartEndE-ValueType
PYRIN 4 87 6.39e-33 SMART
FISNA 135 206 1.45e-22 SMART
Pfam:NACHT 216 385 6.7e-52 PFAM
low complexity region 533 539 N/A INTRINSIC
low complexity region 688 697 N/A INTRINSIC
LRR_RI 737 764 1.07e-9 SMART
LRR 766 793 5.13e1 SMART
LRR 794 821 3.86e-7 SMART
LRR 823 850 1.62e0 SMART
LRR 851 878 3.39e-3 SMART
LRR 880 907 1.2e2 SMART
LRR 908 935 2.24e-3 SMART
LRR 937 964 2.16e2 SMART
LRR 965 992 8.73e-6 SMART
Predicted Effect probably benign

PolyPhen 2 Score 0.009 (Sensitivity: 0.96; Specificity: 0.77)
(Using ENSMUST00000101148)
Meta Mutation Damage Score Not available question?
Is this an essential gene? Probably nonessential (E-score: 0.076) question?
Phenotypic Category Autosomal Semidominant
Candidate Explorer Status loading ...
Single pedigree
Linkage Analysis Data
Penetrance  
Alleles Listed at MGI

All alleles(10) : Targeted, knock-out(3) Targeted, other(4) Chemically induced(3)

Lab Alleles
AlleleSourceChrCoordTypePredicted EffectPPH Score
IGL00421:Nlrp3 APN 11 59456769 missense probably damaging 0.99
IGL00573:Nlrp3 APN 11 59455942 missense possibly damaging 0.93
IGL01025:Nlrp3 APN 11 59442713 missense probably benign 0.21
IGL01637:Nlrp3 APN 11 59440204 missense probably damaging 0.99
IGL02010:Nlrp3 APN 11 59440361 missense probably benign
IGL02334:Nlrp3 APN 11 59455909 missense probably benign
IGL02417:Nlrp3 APN 11 59456849 unclassified probably benign
IGL02578:Nlrp3 APN 11 59439227 missense probably damaging 1.00
IGL02710:Nlrp3 APN 11 59456802 missense probably damaging 0.99
IGL02816:Nlrp3 APN 11 59446608 missense probably benign 0.03
IGL03157:Nlrp3 APN 11 59440372 missense possibly damaging 0.80
IGL03334:Nlrp3 APN 11 59439842 missense probably damaging 1.00
Flogiston UTSW 11 59449274 missense probably benign 0.00
nd1 UTSW 11 59456800 missense probably benign 0.45
Nd14 UTSW 11 59446701 missense possibly damaging 0.89
Nd3 UTSW 11 59456800 missense probably benign 0.45
nd6 UTSW 11 59440180 missense probably damaging 1.00
nd7 UTSW 11 59446701 missense possibly damaging 0.89
Nd9 UTSW 11 59440180 missense probably damaging 1.00
Park2 UTSW 11 59455954 nonsense probably null
Park3 UTSW 11 59456676 missense probably benign 0.02
Park4 UTSW 11 59440357 missense probably benign 0.19
Park5 UTSW 11 59439302 missense probably damaging 0.99
Park6 UTSW 11 59439862 missense probably damaging 1.00
Park7 UTSW 11 59438836 nonsense probably null
Park8 UTSW 11 59457025 missense probably benign 0.19
R0008:Nlrp3 UTSW 11 59449274 missense probably benign 0.00
R0008:Nlrp3 UTSW 11 59449274 missense probably benign 0.00
R0052:Nlrp3 UTSW 11 59455954 nonsense probably null
R0362:Nlrp3 UTSW 11 59439623 missense possibly damaging 0.49
R0416:Nlrp3 UTSW 11 59446750 splice site probably benign
R0649:Nlrp3 UTSW 11 59439368 missense possibly damaging 0.83
R0740:Nlrp3 UTSW 11 59439082 missense probably benign 0.01
R0863:Nlrp3 UTSW 11 59456676 missense probably benign 0.02
R1300:Nlrp3 UTSW 11 59446594 missense possibly damaging 0.86
R1414:Nlrp3 UTSW 11 59440357 missense probably benign 0.19
R1622:Nlrp3 UTSW 11 59439302 missense probably damaging 0.99
R1654:Nlrp3 UTSW 11 59433949 missense probably benign 0.03
R1715:Nlrp3 UTSW 11 59434177 missense probably damaging 1.00
R1754:Nlrp3 UTSW 11 59449228 missense possibly damaging 0.80
R1837:Nlrp3 UTSW 11 59439742 missense probably benign 0.00
R1905:Nlrp3 UTSW 11 59439862 missense probably damaging 1.00
R2281:Nlrp3 UTSW 11 59439962 missense possibly damaging 0.70
R4296:Nlrp3 UTSW 11 59440487 missense possibly damaging 0.89
R4305:Nlrp3 UTSW 11 59438836 nonsense probably null
R4540:Nlrp3 UTSW 11 59442725 missense possibly damaging 0.83
R4591:Nlrp3 UTSW 11 59440048 missense probably benign 0.00
R4816:Nlrp3 UTSW 11 59439127 missense probably benign 0.32
R4913:Nlrp3 UTSW 11 59440064 missense probably benign 0.09
R4970:Nlrp3 UTSW 11 59439554 missense probably damaging 1.00
R5051:Nlrp3 UTSW 11 59457025 missense probably benign 0.19
R5112:Nlrp3 UTSW 11 59439554 missense probably damaging 1.00
R5185:Nlrp3 UTSW 11 59455910 missense probably benign 0.05
R5417:Nlrp3 UTSW 11 59439889 missense probably damaging 1.00
R5709:Nlrp3 UTSW 11 59446574 nonsense probably null
R5869:Nlrp3 UTSW 11 59438960 missense probably damaging 1.00
R5898:Nlrp3 UTSW 11 59437678 missense probably benign 0.00
R5953:Nlrp3 UTSW 11 59437617 missense probably benign
R5979:Nlrp3 UTSW 11 59439797 missense probably benign 0.06
R6359:Nlrp3 UTSW 11 59439392 missense probably damaging 0.97
R6723:Nlrp3 UTSW 11 59456018 missense probably damaging 1.00
R7261:Nlrp3 UTSW 11 59439272 missense possibly damaging 0.83
R7349:Nlrp3 UTSW 11 59438912 missense probably damaging 1.00
R7388:Nlrp3 UTSW 11 59455892 missense probably benign 0.00
R7715:Nlrp3 UTSW 11 59433829 splice site probably null
R7916:Nlrp3 UTSW 11 59442689 missense probably benign 0.00
R8222:Nlrp3 UTSW 11 59439614 missense probably damaging 0.98
R8360:Nlrp3 UTSW 11 59440229 missense probably benign 0.02
R8390:Nlrp3 UTSW 11 59442616 missense possibly damaging 0.47
R8550:Nlrp3 UTSW 11 59440097 missense probably damaging 1.00
R8738:Nlrp3 UTSW 11 59440216 missense probably benign 0.00
R8940:Nlrp3 UTSW 11 59455870 missense probably benign 0.26
R8990:Nlrp3 UTSW 11 59439584 missense probably damaging 0.99
R9324:Nlrp3 UTSW 11 59434141 missense probably damaging 1.00
R9673:Nlrp3 UTSW 11 59440148 missense probably damaging 1.00
RF031:Nlrp3 UTSW 11 59449378 frame shift probably null
RF040:Nlrp3 UTSW 11 59449378 frame shift probably null
Z1088:Nlrp3 UTSW 11 59442686 missense possibly damaging 0.67
Mode of Inheritance Autosomal Semidominant
Local Stock Sperm, gDNA
Repository

none

Last Updated 2019-01-29 1:18 PM by Diantha La Vine
Record Created 2010-02-26 6:08 PM by Hua Huang
Record Posted 2010-10-15
Phenotypic Description
Figure 1.
The ND5 phenotype was initially identified among G3 mice homozygous for mutations induced by N-ethyl-N-nitrosourea (ENU) and tested in the NALP3 Inflammasome Screen.  Peritoneal macrophages isolated from ND5 homozygous mice (G4857 and G4858) secreted reduced amounts of the proinflammatory cytokine interleukin (IL)-1β in response to priming with lipopolysaccharide (LPS) followed by nigericin treatment (Figure 1).  ND5 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

Figure 2. Domain structure of NLRP3. Shown are the pyrin domain (PYD), NACHT domain, NACHT associated domain (NAD), and leucine-rich repeat (LRR) domain. Together, the NACHT and NAD domains are known as the nucleotide-binding domain (NBD). The nd5 mutation causes a tryptophan to arginine substitution at residue 956. This image is interactive. Other mutations found in NLRP3 are noted in red. Click on each mutation for more specific information.

The Nlrp3 gene was directly sequenced as a candidate gene and a T to C transition was found at position 3092 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. 
 

3077 ACCTCACACAGCTGCTGGAATCTCTCCACAATT

951  -T--S--H--S--C--W--N--L--S--T--I- 

 
The mutated nucleotide is indicated in red lettering, and causes a tryptophan to arginine substitution at residue 956 of the NLRP3 protein.
Illustration of Mutations in
Gene & Protein
Protein Prediction
The ND5 mutation results in a tryptophan to arginine change in coding exon 8. Depending on the prediction program used, this residue occurs in the third or second to last leucine rich repeat (LRR). It is likely that this mutation affects the structure and function of the LRR domain, perhaps interfering with binding to factors that stimulate the inflammasome.
 
  Please see the record for ND1 for more information about Nlrp3.
Primers Primers cannot be located by automatic search.
Genotyping
ND5 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. The ND1 primers are used for genotyping.
 
Primers
ND1(F): 5’- ACAGCTTAAAGGCTAAGCCCCTGC -3’
ND1(R): 5’- TTCCACGCCTACCAGGAAATCTCG -3’
 
PCR program
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:
 
                                                                               acagc ttaaaggcta
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
gtggaa
       
Primer binding sites are underlined; sequencing primer binding sites are highlighted in gray; the mutated T is indicated in red.
Science Writers Nora G. Smart
Illustrators Katherine Timer
AuthorsHua Huang, Bruce Beutler
Edit History
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