Phenotypic Mutation 'Pangu' (pdf version)
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AllelePangu
Mutation Type critical splice donor site
Chromosome17
Coordinate56,276,693 bp (GRCm38)
Base Change G ⇒ A (forward strand)
Gene Ticam1
Gene Name toll-like receptor adaptor molecule 1
Synonym(s) TICAM-1, Trif
Chromosomal Location 56,269,319-56,276,786 bp (-)
MGI Phenotype 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]
Accession Number

NCBI RefSeq: NM_174989; MGI:2147032

Mapped Yes 
Amino Acid Change
Institutional SourceBeutler Lab
Ref Sequences
Ensembl: ENSMUSP00000055104 (fasta)
Ensembl: ENSMUSP00000064469 (fasta)
Gene Model not available
SMART Domains

DomainStartEndE-ValueType
Pfam:UNC-93 11 168 1.1e-16 PFAM
transmembrane domain 199 221 N/A INTRINSIC
low complexity region 235 241 N/A INTRINSIC
transmembrane domain 258 275 N/A INTRINSIC
transmembrane domain 290 312 N/A INTRINSIC
transmembrane domain 319 341 N/A INTRINSIC
transmembrane domain 394 416 N/A INTRINSIC
Predicted Effect probably damaging

PolyPhen 2 Score 0.979 (Sensitivity: 0.75; Specificity: 0.96)
(Using Ensembl: ENSMUSP00000064469)
Phenotypic Category
Phenotypequestion? Literature verified References
TLR signaling defect: hyposensitivity to LPS 12855817 12935356
TLR signaling defect: TNF production by macrophages
Penetrance  
Alleles Listed at MGI

All mutations/alleles(11) : Chemically induced (ENU)(1) Gene trapped(4) Targeted(6)

Lab Alleles
AlleleSourceChrCoordTypePredicted EffectPPH Score
IGL02160:Ticam1 APN 17 56270560 missense possibly damaging 0.80
IGL02164:Ticam1 APN 17 56270019 missense unknown
Lps2 UTSW 17 56271577 small deletion
Yue UTSW 17 56271339 missense probably benign 0.06
R0930:Ticam1 UTSW 17 56270226 missense unknown
R0930:Ticam1 UTSW 17 56271687 missense probably damaging 1.00
R1509:Ticam1 UTSW 17 56271113 missense probably benign 0.43
R1837:Ticam1 UTSW 17 56270799 missense possibly damaging 0.87
R1863:Ticam1 UTSW 17 56271436 missense probably damaging 1.00
R1867:Ticam1 UTSW 17 56271718 missense probably benign 0.01
R1872:Ticam1 UTSW 17 56271897 missense probably benign 0.00
R1893:Ticam1 UTSW 17 56271894 missense probably benign 0.36
R1980:Ticam1 UTSW 17 56271555 missense probably damaging 0.99
R1981:Ticam1 UTSW 17 56271555 missense probably damaging 0.99
R1982:Ticam1 UTSW 17 56271555 missense probably damaging 0.99
R2263:Ticam1 UTSW 17 56271888 missense possibly damaging 0.95
R2513:Ticam1 UTSW 17 56271612 missense possibly damaging 0.61
R4294:Ticam1 UTSW 17 56271339 missense probably benign 0.06
R4888:Ticam1 UTSW 17 56271642 missense probably damaging 0.98
R4982:Ticam1 UTSW 17 56272020 missense probably benign 0.10
R5396:Ticam1 UTSW 17 56271117 missense probably benign 0.02
R5604:Ticam1 UTSW 17 56271756 missense probably benign 0.13
R5641:Ticam1 UTSW 17 56270629 frame shift probably null
R5647:Ticam1 UTSW 17 56270629 frame shift probably null
R5648:Ticam1 UTSW 17 56270629 frame shift probably null
R5657:Ticam1 UTSW 17 56270629 frame shift probably null
R5770:Ticam1 UTSW 17 56270629 frame shift probably null
R5771:Ticam1 UTSW 17 56270629 frame shift probably null
R5964:Ticam1 UTSW 17 56271703 missense probably damaging 0.99
R5974:Ticam1 UTSW 17 56271178 missense probably benign
R6217:Ticam1 UTSW 17 56270730 missense probably damaging 1.00
R6983:Ticam1 UTSW 17 56269900 missense probably benign 0.00
R6984:Ticam1 UTSW 17 56269900 missense probably benign 0.00
R6985:Ticam1 UTSW 17 56269900 missense probably benign 0.00
R6986:Ticam1 UTSW 17 56269900 missense probably benign 0.00
R6987:Ticam1 UTSW 17 56269900 missense probably benign 0.00
R6988:Ticam1 UTSW 17 56269900 missense probably benign 0.00
R6989:Ticam1 UTSW 17 56269900 missense probably benign 0.00
V8831:Ticam1 UTSW 17 56269969 frame shift probably null
Mode of Inheritance Autosomal Semidominant
Local Stock
Repository
Last Updated 2016-10-13 3:29 PM by Anne Murray
Record Created 2014-10-03 3:44 PM by Zhao Zhang
Record Posted 2016-09-22
Phenotypic Description
Figure 1. Pangu mice exhibited decreased TNFα secretion in response to TLR4 ligand, LPS. TNFα levels were determined by ELISA. Normalized data are shown. Abbreviations: WT, wild-type; REF, homozygous reference mice; HET, heterozygous variant mice; VAR, homozygous variant mice. Mean (μ) and standard deviation (σ) are indicated.

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
Figure 2. Diagram of the Ticam1 genomic region and the sequenced region. The Pangu mutation is within the donor splice site of intron 1. Exon 1 is non-coding.

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.

 

            <--exon 1 intron 1-->        exon 2-->

60  ……GACCCCTACAGCCAG gtaggatgaaggcaga…… GTCTGTGCTGCC……ATGGATAACCCA……CATCCCATTGG
 1  ……...............                    ............……-M--D--N--P-……...........

 

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.

Protein Prediction
Figure 3. Protein domains of TICAM-1. TICAM-1 (alternatively, TRIF) is a 732-amino acid protein that contains an N- and C-terminal proline-rich domain (PR).  TRIF contains a 200 amino acid Toll/IL-1 receptor (TIR) domain. TRIF has three TRAF6 binding motifs at the N-terminus. The location of the Pangu occurs in the donor splice site of intron 1, before the coding region. Locations of domains/motifs are from Uniprot: Q80UF7. This image is interactive; click to view other TICAM-1 mutations. Click on each mututation for more specific information.

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.

Putative Mechanism

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.
References
Science Writers Anne Murray
Illustrators Peter Jurek, Katherine Timer
AuthorsZhao Zhang, Ying Wang, Hexin Shi, Bruce Beutler
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