Incidental Mutation 'R0066:Ripk2'
| ID |
17190 |
| Institutional Source |
Beutler Lab
|
| Gene Symbol |
Ripk2
|
| Ensembl Gene |
ENSMUSG00000041135 |
| Gene Name |
receptor (TNFRSF)-interacting serine-threonine kinase 2 |
| Synonyms |
2210420D18Rik, D4Bwg0615e, CARDIAK, RICK, CCK, CARD3, RIP2 |
| MMRRC Submission |
038357-MU
|
| Accession Numbers |
|
| Essential gene? |
Possibly non essential
(E-score: 0.301)
|
| Stock # |
R0066 (G1)
|
| Quality Score |
|
|
Status
|
Validated
|
| Chromosome |
4 |
| Chromosomal Location |
16122733-16163647 bp(-) (GRCm39) |
| Type of Mutation |
nonsense |
| DNA Base Change (assembly) |
G to A
at 16123868 bp (GRCm39)
|
| Zygosity |
Heterozygous |
| Amino Acid Change |
Glutamine to Stop codon
at position 436
(Q436*)
|
| Ref Sequence |
ENSEMBL: ENSMUSP00000038833
(fasta)
|
| Gene Model |
predicted gene model for transcript(s):
[ENSMUST00000037035]
[ENSMUST00000183871]
|
| AlphaFold |
P58801 |
| Predicted Effect |
probably null
Transcript: ENSMUST00000037035
AA Change: Q436*
|
| SMART Domains |
Protein: ENSMUSP00000038833
Gene: ENSMUSG00000041135
AA Change: Q436*
| Domain | Start | End | E-Value | Type |
|---|
|
Pfam:Pkinase
|
18 |
289 |
2.1e-43 |
PFAM |
|
Pfam:Pkinase_Tyr
|
18 |
290 |
1.1e-45 |
PFAM |
|
CARD
|
434 |
522 |
2.34e-1 |
SMART |
|
| Predicted Effect |
noncoding transcript
Transcript: ENSMUST00000117437
|
| Predicted Effect |
probably benign
Transcript: ENSMUST00000183871
|
| SMART Domains |
Protein: ENSMUSP00000139381
Gene: ENSMUSG00000041135
| Domain | Start | End | E-Value | Type |
|---|
|
Pfam:Pkinase
|
18 |
290 |
5.6e-46 |
PFAM |
|
Pfam:Pkinase_Tyr
|
18 |
290 |
1.2e-44 |
PFAM |
|
| Meta Mutation Damage Score |
0.9755 |
| Coding Region Coverage |
- 1x: 89.0%
- 3x: 85.6%
- 10x: 75.4%
- 20x: 57.8%
|
| Validation Efficiency |
94% (112/119) |
| MGI Phenotype |
FUNCTION: This gene encodes a member of the receptor-interacting protein family of serine/threonine protein kinases. The encoded protein contains a C-terminal caspase activation and recruitment domain, and is a component of signaling complexes in both the innate and adaptive immune pathways. It is a potent activator of nuclear factor kappa B and inducer of apoptosis in response to various stimuli. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2016]
PHENOTYPE: Homozygous inactivation of this gene leads to impaired cytokine production in response to LPS treatment, and may result in resistance to LPS-induced septic shock and defects in Toll-like receptor and T-cell receptor signaling. Macrophages homozygous for a knock-in allele show normal LPS signaling. [provided by MGI curators]
|
| Allele List at MGI |
All alleles(7) : Targeted(5) Gene trapped(2)
|
| Other mutations in this stock |
Total: 75 list
| Gene | Ref | Var | Chr/Loc | Mutation | Predicted Effect | Zygosity |
|---|
| 1810064F22Rik |
A |
G |
9: 22,119,177 (GRCm39) |
|
noncoding transcript |
Het |
| Aco2 |
T |
C |
15: 81,787,666 (GRCm39) |
|
probably benign |
Het |
| Arsa |
T |
A |
15: 89,358,539 (GRCm39) |
M288L |
possibly damaging |
Het |
| Atg2b |
A |
T |
12: 105,614,708 (GRCm39) |
D1074E |
probably benign |
Het |
| Baiap2l1 |
A |
T |
5: 144,221,372 (GRCm39) |
I174N |
probably damaging |
Het |
| Bptf |
A |
G |
11: 106,952,962 (GRCm39) |
V199A |
possibly damaging |
Het |
| Btn2a2 |
T |
A |
13: 23,662,655 (GRCm39) |
I432L |
probably benign |
Het |
| Ccdc150 |
A |
G |
1: 54,395,850 (GRCm39) |
I778V |
probably benign |
Het |
| Cd200r2 |
G |
A |
16: 44,730,037 (GRCm39) |
V194I |
possibly damaging |
Het |
| Cep350 |
A |
C |
1: 155,786,964 (GRCm39) |
L1421R |
probably damaging |
Het |
| Col6a6 |
A |
T |
9: 105,579,412 (GRCm39) |
C1938S |
probably damaging |
Het |
| Cspg4 |
A |
T |
9: 56,795,418 (GRCm39) |
D1051V |
probably damaging |
Het |
| Cstf1 |
T |
A |
2: 172,214,976 (GRCm39) |
N32K |
probably benign |
Het |
| Ctrb1 |
G |
A |
8: 112,413,269 (GRCm39) |
R248* |
probably null |
Het |
| Cyp2d11 |
T |
A |
15: 82,275,958 (GRCm39) |
M208L |
probably benign |
Het |
| Dbt |
A |
G |
3: 116,337,478 (GRCm39) |
Q334R |
probably benign |
Het |
| Dcaf12 |
A |
G |
4: 41,298,338 (GRCm39) |
V270A |
probably damaging |
Het |
| Dis3l |
T |
A |
9: 64,226,447 (GRCm39) |
N361I |
probably benign |
Het |
| Dnm3 |
A |
G |
1: 162,234,930 (GRCm39) |
V70A |
probably damaging |
Het |
| Dpy19l2 |
G |
A |
9: 24,557,679 (GRCm39) |
|
probably benign |
Het |
| Dst |
C |
A |
1: 34,228,634 (GRCm39) |
H2254N |
possibly damaging |
Het |
| Eif2b1 |
T |
G |
5: 124,711,858 (GRCm39) |
|
probably null |
Het |
| Epm2aip1 |
A |
G |
9: 111,101,531 (GRCm39) |
N168S |
probably benign |
Het |
| Fchsd2 |
A |
G |
7: 100,927,631 (GRCm39) |
Y691C |
possibly damaging |
Het |
| Fndc8 |
A |
T |
11: 82,788,398 (GRCm39) |
D76V |
probably benign |
Het |
| Frmd4a |
T |
C |
2: 4,477,963 (GRCm39) |
L48P |
probably damaging |
Het |
| Gimap6 |
T |
A |
6: 48,679,404 (GRCm39) |
I211F |
probably damaging |
Het |
| Gm15130 |
A |
G |
2: 110,969,284 (GRCm39) |
|
probably benign |
Het |
| Gm19618 |
A |
T |
6: 87,691,227 (GRCm39) |
|
|
Het |
| Gpatch1 |
G |
A |
7: 34,986,652 (GRCm39) |
S768L |
probably damaging |
Het |
| Grb14 |
T |
G |
2: 64,768,836 (GRCm39) |
|
probably null |
Het |
| Hnrnpd |
T |
C |
5: 100,112,560 (GRCm39) |
E222G |
probably damaging |
Het |
| Ighv1-4 |
A |
G |
12: 114,450,989 (GRCm39) |
S40P |
possibly damaging |
Het |
| Kcnh4 |
T |
C |
11: 100,648,626 (GRCm39) |
H26R |
probably benign |
Het |
| Kctd2 |
T |
G |
11: 115,320,343 (GRCm39) |
|
probably benign |
Het |
| Macf1 |
G |
A |
4: 123,325,943 (GRCm39) |
Q3066* |
probably null |
Het |
| Mfn2 |
G |
A |
4: 147,969,902 (GRCm39) |
|
probably benign |
Het |
| Mmab |
T |
C |
5: 114,574,526 (GRCm39) |
|
probably benign |
Het |
| Mrc1 |
T |
C |
2: 14,266,011 (GRCm39) |
S310P |
probably benign |
Het |
| Mrps21 |
T |
C |
3: 95,770,197 (GRCm39) |
Y44C |
probably null |
Het |
| Myh10 |
T |
A |
11: 68,590,317 (GRCm39) |
F121Y |
probably damaging |
Het |
| Myo1f |
A |
G |
17: 33,820,677 (GRCm39) |
D840G |
probably damaging |
Het |
| Nol6 |
G |
T |
4: 41,119,572 (GRCm39) |
|
probably benign |
Het |
| Ntsr2 |
T |
C |
12: 16,704,120 (GRCm39) |
I207T |
probably benign |
Het |
| Nwd1 |
T |
A |
8: 73,438,484 (GRCm39) |
S1552T |
probably benign |
Het |
| Or11j4 |
T |
A |
14: 50,630,659 (GRCm39) |
F149I |
probably benign |
Het |
| Pkd1l3 |
G |
T |
8: 110,347,103 (GRCm39) |
G159C |
unknown |
Het |
| Plcb4 |
T |
C |
2: 135,803,689 (GRCm39) |
S521P |
probably benign |
Het |
| Plcl1 |
A |
T |
1: 55,752,634 (GRCm39) |
I993F |
probably damaging |
Het |
| Plekha7 |
T |
C |
7: 115,756,743 (GRCm39) |
S640G |
probably damaging |
Het |
| Ptprn2 |
A |
C |
12: 117,240,222 (GRCm39) |
N993T |
probably benign |
Het |
| Reck |
A |
G |
4: 43,930,936 (GRCm39) |
N646D |
probably damaging |
Het |
| Rfx2 |
A |
T |
17: 57,093,736 (GRCm39) |
|
probably benign |
Het |
| Ryr1 |
C |
T |
7: 28,704,992 (GRCm39) |
|
probably benign |
Het |
| Sema6b |
A |
G |
17: 56,435,271 (GRCm39) |
V324A |
possibly damaging |
Het |
| Sik2 |
C |
A |
9: 50,909,833 (GRCm39) |
M73I |
probably benign |
Het |
| Slc39a6 |
T |
C |
18: 24,732,326 (GRCm39) |
K321E |
probably damaging |
Het |
| Slc7a4 |
C |
A |
16: 17,391,875 (GRCm39) |
V520F |
probably benign |
Het |
| Sptan1 |
C |
A |
2: 29,893,679 (GRCm39) |
|
probably benign |
Het |
| Stab1 |
C |
T |
14: 30,879,027 (GRCm39) |
|
probably benign |
Het |
| Tbc1d17 |
C |
T |
7: 44,493,495 (GRCm39) |
|
probably benign |
Het |
| Tbcd |
T |
A |
11: 121,394,590 (GRCm39) |
L49* |
probably null |
Het |
| Tulp4 |
A |
T |
17: 6,252,008 (GRCm39) |
N60I |
probably damaging |
Het |
| Ubqlnl |
A |
T |
7: 103,798,145 (GRCm39) |
W451R |
probably damaging |
Het |
| Usp53 |
G |
T |
3: 122,746,956 (GRCm39) |
C363* |
probably null |
Het |
| Utp4 |
A |
G |
8: 107,649,530 (GRCm39) |
T660A |
possibly damaging |
Het |
| Vmn1r194 |
A |
T |
13: 22,428,641 (GRCm39) |
Y86F |
probably benign |
Het |
| Vmn1r195 |
A |
T |
13: 22,463,409 (GRCm39) |
H293L |
possibly damaging |
Het |
| Vmn1r231 |
T |
C |
17: 21,109,998 (GRCm39) |
R306G |
probably benign |
Het |
| Vmn2r77 |
T |
C |
7: 86,449,964 (GRCm39) |
V70A |
probably benign |
Het |
| Vps8 |
A |
G |
16: 21,296,273 (GRCm39) |
E515G |
possibly damaging |
Het |
| Wdr18 |
C |
A |
10: 79,796,937 (GRCm39) |
Y104* |
probably null |
Het |
| Xab2 |
A |
T |
8: 3,663,880 (GRCm39) |
N346K |
probably damaging |
Het |
| Zdhhc12 |
C |
T |
2: 29,982,547 (GRCm39) |
R50H |
probably damaging |
Het |
| Zdhhc8 |
A |
G |
16: 18,043,064 (GRCm39) |
S379P |
probably benign |
Het |
|
| Other mutations in Ripk2 |
| Allele | Source | Chr | Coord | Type | Predicted Effect | PPH Score |
|---|
|
IGL01290:Ripk2
|
APN |
4 |
16,139,198 (GRCm39) |
splice site |
probably benign |
|
|
IGL01346:Ripk2
|
APN |
4 |
16,132,775 (GRCm39) |
critical splice donor site |
probably null |
|
|
IGL01631:Ripk2
|
APN |
4 |
16,163,342 (GRCm39) |
missense |
possibly damaging |
0.83 |
|
IGL02151:Ripk2
|
APN |
4 |
16,139,240 (GRCm39) |
missense |
possibly damaging |
0.83 |
|
IGL03093:Ripk2
|
APN |
4 |
16,152,056 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R0066:Ripk2
|
UTSW |
4 |
16,123,868 (GRCm39) |
nonsense |
probably null |
|
|
R0189:Ripk2
|
UTSW |
4 |
16,129,125 (GRCm39) |
splice site |
probably null |
|
|
R1454:Ripk2
|
UTSW |
4 |
16,163,239 (GRCm39) |
missense |
probably damaging |
0.96 |
|
R1715:Ripk2
|
UTSW |
4 |
16,155,192 (GRCm39) |
critical splice acceptor site |
probably null |
|
|
R2153:Ripk2
|
UTSW |
4 |
16,132,775 (GRCm39) |
critical splice donor site |
probably null |
|
|
R2266:Ripk2
|
UTSW |
4 |
16,152,011 (GRCm39) |
missense |
possibly damaging |
0.91 |
|
R2394:Ripk2
|
UTSW |
4 |
16,132,774 (GRCm39) |
splice site |
probably benign |
|
|
R3693:Ripk2
|
UTSW |
4 |
16,127,695 (GRCm39) |
missense |
probably benign |
|
|
R4412:Ripk2
|
UTSW |
4 |
16,124,511 (GRCm39) |
missense |
probably benign |
|
|
R4463:Ripk2
|
UTSW |
4 |
16,151,968 (GRCm39) |
missense |
possibly damaging |
0.70 |
|
R4843:Ripk2
|
UTSW |
4 |
16,155,073 (GRCm39) |
missense |
probably damaging |
0.99 |
|
R5085:Ripk2
|
UTSW |
4 |
16,127,663 (GRCm39) |
missense |
possibly damaging |
0.78 |
|
R5453:Ripk2
|
UTSW |
4 |
16,151,989 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R6197:Ripk2
|
UTSW |
4 |
16,163,330 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R6576:Ripk2
|
UTSW |
4 |
16,131,558 (GRCm39) |
splice site |
probably null |
|
|
R6967:Ripk2
|
UTSW |
4 |
16,158,275 (GRCm39) |
critical splice donor site |
probably null |
|
|
R7351:Ripk2
|
UTSW |
4 |
16,155,048 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R7479:Ripk2
|
UTSW |
4 |
16,155,154 (GRCm39) |
missense |
probably benign |
0.02 |
|
R7718:Ripk2
|
UTSW |
4 |
16,151,968 (GRCm39) |
missense |
possibly damaging |
0.70 |
|
R8188:Ripk2
|
UTSW |
4 |
16,139,218 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R8242:Ripk2
|
UTSW |
4 |
16,124,430 (GRCm39) |
missense |
probably benign |
0.00 |
|
R8509:Ripk2
|
UTSW |
4 |
16,124,436 (GRCm39) |
missense |
probably benign |
|
|
R8700:Ripk2
|
UTSW |
4 |
16,158,422 (GRCm39) |
missense |
possibly damaging |
0.91 |
|
R8987:Ripk2
|
UTSW |
4 |
16,123,699 (GRCm39) |
missense |
possibly damaging |
0.72 |
|
R9084:Ripk2
|
UTSW |
4 |
16,123,795 (GRCm39) |
missense |
probably damaging |
1.00 |
|
R9202:Ripk2
|
UTSW |
4 |
16,124,502 (GRCm39) |
missense |
probably benign |
|
|
R9369:Ripk2
|
UTSW |
4 |
16,127,651 (GRCm39) |
missense |
probably benign |
0.01 |
|
R9469:Ripk2
|
UTSW |
4 |
16,138,181 (GRCm39) |
missense |
possibly damaging |
0.73 |
|
Z1176:Ripk2
|
UTSW |
4 |
16,151,943 (GRCm39) |
missense |
probably damaging |
1.00 |
|
Z1177:Ripk2
|
UTSW |
4 |
16,163,331 (GRCm39) |
missense |
probably benign |
0.21 |
|
| Protein Function and Prediction |
Ripk2 encodes receptor-interacting protein 2 (RIP2; alternatively, RICK or CARD3), a serine/threonine kinase. RIP2 has a N-terminal serine/threonine kinase catalytic domain and a C-terminal caspase activation and recruitment domain (CARD) (1). The CARD domain can mediate interactions that facilitate the recruitment of caspases to receptor complexes (1). RIP2 promotes the activation of caspase-8 and RIP2 expression can potentiate FAS-, FADD- or caspase-8-induced apoptosis (1;2). RIP2 also binds TRAF3, a protein that positively regulates type I interferon production and negatively regulate the activation of mitogen-activated protein kinase (3). Ripk2 knockdown results in increased TRAF3 expression and the suppression of the alternative NF-кB pathway (3). Additional proposed immune functions include the mediation of TLR and Nod-like receptor signaling (4). Studies with Ripk2-/- macrophages showed that Rip2 regulates TLR4-dependent macropinocytosis of LDL in macrophages and is proposed to function in a protective role during aterogenesis (4).
|
| Expression/Localization |
In human tissues, RIPK2 produces two transcripts due to alternative polyadenylation (1). Both transcripts are expressed in various tissues including spleen, peripheral blood leukocytes, placenta, testis, and heart (1;2). Rip2 expression is upregulated by inflammatory cytokines that activate the NF-κB pathway (4).
|
| Background |
RIPK2 expression is upregulated in several human conditions including sepsis, Huntington’s disease, Alzheimer’s disease and neuronal hypoxia (3;5-7).
Ripk2tm1Cfl/tm1Cfl; MGI: 3622328
involves: 129S5/SvEvBrd
Macrophages from homozygous animals exhibited decreased LPS-induced TNF-a and IL-6 production (8)
Ripk2tm1Flv/tm1Flv; MGI:2660793
involves: 129S1/Sv
Homozygotes displayed reduced T-cell proliferation and reduced IFN-gamma production after stimulation with IL-18 or IL-12 (9). Homzygotes also exhibited decreased IL-6 and TNF secretion following TLR stimulation (9).
Ripk2tm1Flv/tm1Flv; MGI:2660793
involves: 129S1/Sv * C57BL/6
In this genetic background, homozygotes exhibited abnormal IL-6 and TNF production by macrophages following exposure to L. monocytogenes (10).
Ripk2tm1Ghc/tm1Ghc; MGI:2446070
involves: 129S4/SvJae * C57BL/6
Homozygotes exhibited decreased T-cell proliferation, decreased IgG2a levels, decreased IFN-gamma secretion, and increased susceptibility to infection (11).
|
| References |
1. Inohara, N., del Peso, L., Koseki, T., Chen, S., and Nunez, G. (1998) RICK, a Novel Protein Kinase Containing a Caspase Recruitment Domain, Interacts with CLARP and Regulates CD95-Mediated Apoptosis. J Biol Chem. 273, 12296-12300.
3. Cai, X., Du, J., Liu, Y., Xia, W., Liu, J., Zou, M., Wang, Y., Wang, M., Su, H., and Xu, D. (2013) Identification and Characterization of Receptor-Interacting Protein 2 as a TNFR-Associated Factor 3 Binding Partner. Gene. 517, 205-211.
4. Levin, M. C., Jirholt, P., Wramstedt, A., Johansson, M. E., Lundberg, A. M., Trajkovska, M. G., Stahlman, M., Fogelstrand, P., Brisslert, M., Fogelstrand, L., Yan, Z. Q., Hansson, G. K., Bjorkbacka, H., Olofsson, S. O., and Boren, J. (2011) Rip2 Deficiency Leads to Increased Atherosclerosis Despite Decreased Inflammation. Circ Res. 109, 1210-1218.
6. Engidawork, E., Gulesserian, T., Yoo, B. C., Cairns, N., and Lubec, G. (2001) Alteration of Caspases and Apoptosis-Related Proteins in Brains of Patients with Alzheimer's Disease. Biochem Biophys Res Commun. 281, 84-93.
7. Wang, X., Wang, H., Figueroa, B. E., Zhang, W. H., Huo, C., Guan, Y., Zhang, Y., Bruey, J. M., Reed, J. C., and Friedlander, R. M. (2005) Dysregulation of Receptor Interacting Protein-2 and Caspase Recruitment Domain Only Protein Mediates Aberrant Caspase-1 Activation in Huntington's Disease. J Neurosci. 25, 11645-11654.
8. Lu, C., Wang, A., Dorsch, M., Tian, J., Nagashima, K., Coyle, A. J., Jaffee, B., Ocain, T. D., and Xu, Y. (2005) Participation of Rip2 in Lipopolysaccharide Signaling is Independent of its Kinase Activity. J Biol Chem. 280, 16278-16283.
9. Kobayashi, K., Inohara, N., Hernandez, L. D., Galan, J. E., Nunez, G., Janeway, C. A., Medzhitov, R., and Flavell, R. A. (2002) RICK/Rip2/CARDIAK Mediates Signalling for Receptors of the Innate and Adaptive Immune Systems. Nature. 416, 194-199.
10. Kim, Y. G., Park, J. H., Shaw, M. H., Franchi, L., Inohara, N., and Nunez, G. (2008) The Cytosolic Sensors Nod1 and Nod2 are Critical for Bacterial Recognition and Host Defense After Exposure to Toll-Like Receptor Ligands. Immunity. 28, 246-257.
11. Chin, A. I., Dempsey, P. W., Bruhn, K., Miller, J. F., Xu, Y., and Cheng, G. (2002) Involvement of Receptor-Interacting Protein 2 in Innate and Adaptive Immune Responses. Nature. 416, 190-194. |
| Posted On |
2013-01-20 |
| Science Writer |
Anne Murray |
Incidental Mutation