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|Mutation Type||critical splice donor site|
|Coordinate||56,276,693 bp (GRCm38)|
|Base Change||G ⇒ A (forward strand)|
|Gene Name||toll-like receptor adaptor molecule 1|
|Chromosomal Location||56,269,319-56,276,786 bp (-)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene encodes an adaptor protein containing a Toll/interleukin-1 receptor (TIR) homology domain, which is an intracellular signaling domain that mediates protein-protein interactions between the Toll-like receptors (TLRs) and signal-transduction components. This protein is involved in native immunity against invading pathogens. It specifically interacts with toll-like receptor 3, but not with other TLRs, and this association mediates dsRNA induction of interferon-beta through activation of nuclear factor kappa-B, during an antiviral immune response. [provided by RefSeq, Jan 2012]
PHENOTYPE: Homozygous null mice are viable but exhibit abnormalities of the innate immune system. [provided by MGI curators]
|Amino Acid Change|
|Institutional Source||Beutler Lab|
Ensembl: ENSMUSP00000055104 (fasta)
Ensembl: ENSMUSP00000064469 (fasta)
|Gene Model||not available|
|Predicted Effect||probably damaging
PolyPhen 2 Score 0.979 (Sensitivity: 0.75; Specificity: 0.96)
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Semidominant|
|Last Updated||2016-10-13 3:29 PM by Anne Murray|
|Record Created||2014-10-03 3:44 PM by Zhao Zhang|
The Pangu phenotype was identified among G3 mice of the pedigree R0893, some of which exhibited decreased tumor necrosis factor (TNF)-α production in response to TLR4 ligand, lipopolysaccharide (LPS) (Figure 1).
|Nature of Mutation|
The Pangu mutation was mapped to chromosome 17. Ticam1 was sequenced but no mutation found after 99% coverage. The Pangu allele failed to complement the Ticam1 mutant allele Lps2, demonstrating that Pangu and Lps2 mice harbor mutations in the same gene. PCR amplification and sequencing of the complete Ticam1 genomic region, including the region before the 5’-UTR, revealed a G to A transition at base pair 56,276,693 (v38) on chromosome 17, or base pair 75 in the GenBank genomic region NC_000083 within the donor splice site of intron 1 (Figure 2). The effect of the mutation at the cDNA and protein level have not examined, but the mutation is predicted to result in aberrant splicing.
Genomic numbering corresponds to NC_000083. The donor splice site of intron 1, which is destroyed by the Pangu mutation, is indicated in blue lettering and the mutated nucleotide is indicated in red.
Ticam1 encodes the 732-amino acid protein TICAM-1 [Toll-interleukin 1 receptor (TIR) domain-containing adaptor molecule-1; hereafter TRIF (TIR domain-containing adaptor inducing IFN-β)], an adaptor in TLR3 and TLR4 signaling (Figure 3). Mouse TRIF contains a conserved C-terminal proline-rich domain. TRIF also contains a Toll/IL-1 receptor (TIR) domain, a conserved region of approximately 200 amino acids which mediates homo- and heterotypic protein interactions during signal transduction (1;2). TRIF reportedly harbors between one and three TNF receptor-associated factor-6 (TRAF6) binding motifs at its N-terminus (3;4), defined by the sequence P-X-E-X-X-acidic/aromatic (5).
Please see the record Lps2 for more information about Ticam1.
The twelve mouse TLRs and ten human TLRs recognize a wide range of structurally distinct molecules, and all signal through only four adaptor proteins known to date: MyD88, Tirap (Mal), TICAM-1 (TRIF) and TRAM (6). TRIF and MyD88, act in LPS-induced TLR4 signaling leading to NF-κB and IRF-3 activation, and upregulation of costimulatory molecules (7-9). The TRIF-mediated MyD88-independent pathway induces a late-phase activation of NF-κB and MAP kinases. LPS-induced cytokine production is nearly abolished in Trif mutants (7;9;10). TRIF is the only adaptor serving TLR3 (7;9). Lps2 or Trif-null macrophages fail to activate NF-κB or IRF-3, or induce IFN-β in response to poly I:C (7;9). Similar to the Lps2 mice, Pangu mice have reduced TNF-α production in response to LPS, indicating reduced TRIFPangu function. The pangu mice were not assessed for IFN-β induction in response to poly I:C.
|Primers||Primers cannot be located by automatic search.|
1. Oshiumi, H., Matsumoto, M., Funami, K., Akazawa, T., and Seya, T. (2003) TICAM-1, an Adaptor Molecule that Participates in Toll-Like Receptor 3-Mediated Interferon-Beta Induction. Nat Immunol. 4, 161-171.
2. Yamamoto, M., Sato, S., Mori, K., Hoshino, K., Takeuchi, O., Takeda, K., and Akira, S. (2002) Cutting Edge: A Novel Toll/IL-1 Receptor Domain-Containing Adapter that Preferentially Activates the IFN-Beta Promoter in the Toll-Like Receptor Signaling. J Immunol. 169, 6668-6672.
3. Sato, S., Sugiyama, M., Yamamoto, M., Watanabe, Y., Kawai, T., Takeda, K., and Akira, S. (2003) Toll/IL-1 Receptor Domain-Containing Adaptor Inducing IFN-Beta (TRIF) Associates with TNF Receptor-Associated Factor 6 and TANK-Binding Kinase 1, and Activates Two Distinct Transcription Factors, NF-Kappa B and IFN-Regulatory Factor-3, in the Toll-Like Receptor Signaling. J Immunol. 171, 4304-4310.
4. Jiang, Z., Mak, T. W., Sen, G., and Li, X. (2004) Toll-Like Receptor 3-Mediated Activation of NF-kappaB and IRF3 Diverges at Toll-IL-1 Receptor Domain-Containing Adapter Inducing IFN-Beta. Proc Natl Acad Sci U S A. 101, 3533-3538.
5. Ye, H., Arron, J. R., Lamothe, B., Cirilli, M., Kobayashi, T., Shevde, N. K., Segal, D., Dzivenu, O. K., Vologodskaia, M., Yim, M., Du, K., Singh, S., Pike, J. W., Darnay, B. G., Choi, Y., and Wu, H. (2002) Distinct Molecular Mechanism for Initiating TRAF6 Signalling. Nature. 418, 443-447.
6. Beutler, B., Jiang, Z., Georgel, P., Crozat, K., Croker, B., Rutschmann, S., Du, X., and Hoebe, K. (2006) Genetic Analysis of Host Resistance: Toll-Like Receptor Signaling and Immunity at Large. Annu Rev Immunol. 24, 353-389.
7. Hoebe, K., Du, X., Georgel, P., Janssen, E., Tabeta, K., Kim, S. O., Goode, J., Lin, P., Mann, N., Mudd, S., Crozat, K., Sovath, S., Han, J., and Beutler, B. (2003) Identification of Lps2 as a Key Transducer of MyD88-Independent TIR Signaling. Nature. 424, 743-748.
8. Hoebe, K., Jannsen, E. M., Kim, S. O., Alexopoulou, L., Flavell, R. A., Han, J., and Beutler, B. (2003) Upregulation of Costimulatory Molecules Induced by Lipopolysaccharide and Double-Stranded RNA Occurs by Trif-Dependent and Trif-Independent Pathways. Nat Immunol. 4, 1223-1229.
9. Yamamoto, M., Sato, S., Hemmi, H., Hoshino, K., Kaisho, T., Sanjo, H., Takeuchi, O., Sugiyama, M., Okabe, M., Takeda, K., and Akira, S. (2003) Role of Adaptor TRIF in the MyD88-Independent Toll-Like Receptor Signaling Pathway. Science. 301, 640-643.
|Science Writers||Anne Murray|
|Illustrators||Peter Jurek, Katherine Timer|
|Authors||Zhao Zhang, Ying Wang, Hexin Shi, Bruce Beutler|
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