Incidental Mutation 'E2594:Rigi'
ID 2
Institutional Source Beutler Lab
Gene Symbol Rigi
Ensembl Gene ENSMUSG00000040296
Gene Name RNA sensor RIG-I
Synonyms RIG-I, DEAD (Asp-Glu-Ala-Asp) box polypeptide 58, Ddx58, 6430573D20Rik
Accession Numbers
Essential gene? Probably non essential (E-score: 0.148) question?
Stock # E2594 of strain daniel_gray
Quality Score
Status Validated
Chromosome 4
Chromosomal Location 40203773-40239828 bp(-) (GRCm39)
Type of Mutation nonsense
DNA Base Change (assembly) C to T at 40235282 bp (GRCm39)
Zygosity Heterozygous
Amino Acid Change Tryptophan to Stop codon at position 69 (W69*)
Ref Sequence ENSEMBL: ENSMUSP00000042433 (fasta)
Gene Model predicted gene model for transcript(s): [ENSMUST00000037907] [ENSMUST00000142055]
AlphaFold Q6Q899
PDB Structure Mouse RIG-I ATPase Domain [X-RAY DIFFRACTION]
Predicted Effect probably null
Transcript: ENSMUST00000037907
AA Change: W69*
SMART Domains Protein: ENSMUSP00000042433
Gene: ENSMUSG00000040296
AA Change: W69*

DomainStartEndE-ValueType
Pfam:CARD_2 1 93 1.2e-31 PFAM
Pfam:CARD_2 99 189 6.2e-28 PFAM
DEXDc 240 453 8.61e-26 SMART
low complexity region 582 600 N/A INTRINSIC
HELICc 642 735 1.32e-12 SMART
Pfam:RIG-I_C-RD 807 924 4.4e-39 PFAM
Predicted Effect noncoding transcript
Transcript: ENSMUST00000127026
Predicted Effect noncoding transcript
Transcript: ENSMUST00000139583
Predicted Effect probably benign
Transcript: ENSMUST00000142055
SMART Domains Protein: ENSMUSP00000115052
Gene: ENSMUSG00000040296

DomainStartEndE-ValueType
PDB:4NQK|D 1 153 3e-53 PDB
DEXDc 195 408 8.61e-26 SMART
low complexity region 537 555 N/A INTRINSIC
HELICc 597 690 1.32e-12 SMART
Predicted Effect noncoding transcript
Transcript: ENSMUST00000149539
Meta Mutation Damage Score 0.9756 question?
Coding Region Coverage
  • 1x: 80.5%
  • 3x: 47.5%
Validation Efficiency 94% (32/34)
MGI Phenotype FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases which are implicated in a number of cellular processes involving RNA binding and alteration of RNA secondary structure. This gene encodes a protein containing RNA helicase-DEAD box protein motifs and a caspase recruitment domain (CARD). It is involved in viral double-stranded (ds) RNA recognition and the regulation of immune response. [provided by RefSeq, Jul 2008]
PHENOTYPE: Most homozygotes for a null allele die in utero with liver apoptosis while survivors show impaired IFN induction and succumb to infection with certain RNA viruses. Homozygotes for another null allele are viable but develop colitis and progressive granulocytosis leading to chronic myeloid leukemia. [provided by MGI curators]
Allele List at MGI

All alleles(9) : Targeted, knock-out(2) Gene trapped(7)

Other mutations in this stock
Total: 3 list
GeneRefVarChr/LocMutationPredicted EffectZygosity
Adamts17 A G 7: 66,654,098 (GRCm39) S443G probably damaging Homo
Atad3a G A 4: 155,835,390 (GRCm39) probably benign Het
Misp3 G A 8: 84,737,331 (GRCm39) probably benign Het
Other mutations in Rigi
AlleleSourceChrCoordTypePredicted EffectPPH Score
IGL00662:Rigi APN 4 40,220,389 (GRCm39) splice site probably benign
IGL01344:Rigi APN 4 40,208,883 (GRCm39) missense probably damaging 0.99
IGL01414:Rigi APN 4 40,222,176 (GRCm39) missense probably damaging 1.00
IGL01529:Rigi APN 4 40,225,685 (GRCm39) missense probably benign
IGL01756:Rigi APN 4 40,209,934 (GRCm39) missense probably damaging 1.00
IGL02023:Rigi APN 4 40,216,487 (GRCm39) missense possibly damaging 0.76
IGL02223:Rigi APN 4 40,209,993 (GRCm39) missense possibly damaging 0.48
IGL02458:Rigi APN 4 40,229,536 (GRCm39) missense probably damaging 0.98
IGL02937:Rigi APN 4 40,229,661 (GRCm39) missense probably benign 0.00
IGL03358:Rigi APN 4 40,206,069 (GRCm39) missense possibly damaging 0.54
R0324:Rigi UTSW 4 40,213,766 (GRCm39) missense probably benign 0.24
R0400:Rigi UTSW 4 40,235,257 (GRCm39) missense probably benign 0.00
R0518:Rigi UTSW 4 40,216,354 (GRCm39) critical splice donor site probably null
R0834:Rigi UTSW 4 40,239,596 (GRCm39) missense possibly damaging 0.64
R1474:Rigi UTSW 4 40,208,868 (GRCm39) missense possibly damaging 0.62
R1611:Rigi UTSW 4 40,223,862 (GRCm39) missense probably damaging 1.00
R1803:Rigi UTSW 4 40,224,013 (GRCm39) missense probably benign 0.00
R1906:Rigi UTSW 4 40,206,054 (GRCm39) missense probably benign 0.01
R2072:Rigi UTSW 4 40,224,069 (GRCm39) splice site probably null
R4696:Rigi UTSW 4 40,203,798 (GRCm39) unclassified probably benign
R4860:Rigi UTSW 4 40,210,000 (GRCm39) missense probably damaging 0.97
R4860:Rigi UTSW 4 40,210,000 (GRCm39) missense probably damaging 0.97
R5027:Rigi UTSW 4 40,208,845 (GRCm39) missense probably benign
R5568:Rigi UTSW 4 40,222,140 (GRCm39) missense probably benign
R6144:Rigi UTSW 4 40,229,551 (GRCm39) missense probably benign 0.21
R6341:Rigi UTSW 4 40,222,199 (GRCm39) critical splice acceptor site probably null
R6373:Rigi UTSW 4 40,216,487 (GRCm39) missense possibly damaging 0.76
R6454:Rigi UTSW 4 40,220,456 (GRCm39) missense probably damaging 0.99
R6456:Rigi UTSW 4 40,213,838 (GRCm39) missense possibly damaging 0.73
R6523:Rigi UTSW 4 40,205,947 (GRCm39) missense probably benign 0.00
R6593:Rigi UTSW 4 40,226,651 (GRCm39) missense probably benign 0.02
R6741:Rigi UTSW 4 40,211,624 (GRCm39) missense probably damaging 1.00
R6964:Rigi UTSW 4 40,225,697 (GRCm39) missense probably benign 0.00
R7149:Rigi UTSW 4 40,222,079 (GRCm39) missense possibly damaging 0.64
R7159:Rigi UTSW 4 40,213,804 (GRCm39) missense probably benign 0.29
R7237:Rigi UTSW 4 40,205,938 (GRCm39) missense probably benign 0.10
R7352:Rigi UTSW 4 40,239,668 (GRCm39) missense probably benign 0.00
R7356:Rigi UTSW 4 40,226,600 (GRCm39) missense probably benign 0.01
R7611:Rigi UTSW 4 40,225,651 (GRCm39) missense probably damaging 1.00
R7615:Rigi UTSW 4 40,229,653 (GRCm39) missense possibly damaging 0.59
R7729:Rigi UTSW 4 40,206,034 (GRCm39) missense possibly damaging 0.53
R7759:Rigi UTSW 4 40,225,104 (GRCm39) missense probably damaging 1.00
R7800:Rigi UTSW 4 40,211,618 (GRCm39) missense probably benign 0.35
R7965:Rigi UTSW 4 40,223,824 (GRCm39) nonsense probably null
R7976:Rigi UTSW 4 40,209,894 (GRCm39) missense probably damaging 1.00
R8531:Rigi UTSW 4 40,225,596 (GRCm39) critical splice donor site probably null
R8978:Rigi UTSW 4 40,239,650 (GRCm39) missense probably damaging 0.99
R8994:Rigi UTSW 4 40,205,941 (GRCm39) nonsense probably null
R9052:Rigi UTSW 4 40,208,459 (GRCm39) missense probably benign 0.03
R9164:Rigi UTSW 4 40,208,827 (GRCm39) missense probably damaging 0.99
R9394:Rigi UTSW 4 40,213,831 (GRCm39) missense probably damaging 0.98
R9431:Rigi UTSW 4 40,229,545 (GRCm39) missense probably benign 0.00
R9645:Rigi UTSW 4 40,220,437 (GRCm39) missense possibly damaging 0.80
Nature of Mutation
DNA sequencing using the SOLiD technique identified a G to A transition at position 212 of the Ddx58 transcript, in exon 2 of 18 total exons (Figure 1).  Multiple isoforms of Ddx58 are displayed in Ensembl.
 
195 CTGCAGTCAGAGGGCTGGTTCCAGGCCTTTTTG
64  -L--Q--S--E--G--W--F--Q--A--F--L-
 
The mutated nucleotide is indicated in red lettering, and creates a premature stop codon at amino acid 69 (normally a tryptophan) deleting 858 amino acids from the C-terminus of the encoded protein.  The mutation has been confirmed by DNA sequencing using the Sanger method (Figure 2).
Protein Function and Prediction
Ddx58 encodes a DEAD (Asp-Glu-Ala-Asp) box protein that is a member of the helicase superfamily.  Helicases are ATP-dependent enzymes involved in binding to and unwinding nucleic acids. The DEAD box helicases are involved in various aspects of RNA metabolism.  Ddx58 or RIG-I (retinoic acid inducible gene I) is involved in the innate immune defense against viruses and other pathogenic organisms. Interaction with pathogenic double-stranded (ds)RNA triggers a transduction cascade involving the mitochondrial antiviral signaling (MAVS) protein (also known as IPS-1, Cardif, and VISA), which results in the activation of NF-κB, interferon response factor 3 (IRF3) and IRF7 and the induction of the expression of antiviral cytokines such as IFN-β and RANTES (CCL5).  RIG-I is essential for the production of interferons in response to RNA viruses including paramyxoviruses, and possibly other negative strand RNA viruses.
 
The RIG-I protein contains several domains including the DEAD box helicase domain involved in recognizing dsRNA, two N-terminal caspase activation and recruitment domains (CARDs) that interact with and signal through MAVS, and a zinc-binding C-terminal regulatory domain (RD) that is implicated in inhibiting downstream signaling but is also necessary for RNA sensing (Uniprot Q6Q899). The RD domain binds to 5’-triphosphate containing RNAs, and the crystal structure reveals a zinc-binding domain that is structurally related to GDP/GTP exchange factors of Rab-like GTPases consisting of two four-stranded (β1, β2, β9, β10, and β5, β6, β7, β8) and one two-stranded (β3, β4) antiparallel β sheets. The two four-stranded β sheets are connected by two loops, each containing two highly conserved cysteine residues (Cys811, Cys814 and Cys865, Cys870), which coordinate zinc (1) (Figure 3).
References

1. Cui, S., Eisenacher, K., Kirchhofer, A., Brzozka, K., Lammens, A., Lammens, K., Fujita, T., Conzelmann, K. K., Krug, A., and Hopfner, K. P. (2008) The C-Terminal Regulatory Domain is the RNA 5'-Triphosphate Sensor of RIG-I. Mol. Cell. 29, 169-179.

Posted On 2009-10-27