ライフサイエンスコーパス: IFIH1

1 prevent activation of the dsRNA sensor MDA5 (Ifih1).

2 feron induced with helicase C domain 1 gene (IFIH1).

3 cases RIG-I (also known as DDX58) and MDA-5 (IFIH1).

4 FCRL3 and 11q13/RELA, and for PCAs with 2q24/IFIH1.

5 ation-associated gene 5 (MDA5, also known as Ifih1), a conventional innate immune regulator following

6 ma differentiation-associated gene 5 (MDA-5, IFIH1), a cytosolic innate pattern recognition receptor,

7 Variants in IFIH1, a gene coding the cytoplasmatic RNA sensor MDA5,

8 nic mouse line containing multiple copies of Ifih1, a gene encoding the cytoplasmic dsRNA sensor MDA5

9 We also found that IFIH1, a susceptibility gene of type 1 diabetes, interac

10 MDA5 variants encoded by minor IFIH1 alleles associated with lower T1D risk exhibit red

11 Functional testing of the variants IFIH1 alleles demonstrated that the resulting proteins a

12 cytosolic double-stranded RNA receptor gene IFIH1 (also called MDA5) cause a spectrum of neuroimmuno

13 nate immunity viral RNA receptor gene region IFIH1 (also known as mda-5 or Helicard) on chromosome 2q

14 as three novel secondary associations within IFIH1 and IL12B.

15 organization, we prioritize genes (including IFIH1 and IL23A) that have implications for common molec

16 rotective rare and low-frequency variants in IFIH1 and TYK2 disrupt conserved protein domains, highli

17 strates a high degree of concordance on both Ifih1 (+/+) and Ifih1 (-/-) backgrounds, suggesting no s

18 I (also known as DDX58), MDA5 (also known as IFIH1) and IFITM3, whereas more targeted antiviral speci

19 We report both common (e.g., Y13N in IFIH1) and rare variants in these proteins and discuss t

20 egulatory pathways for innate immunity (e.g. IFIH1), and HIV-1 viral load modulation (e.g. CCR5).

21 n of antiviral sensors [RIG-I (DDX58), MDA5 (IFIH1), and LGP2 (DHX58)], transactivators (STAT1, IRF7,

22 eported type 1 diabetes associations at INS, IFIH1, and KIAA0350 and identify an additional disease a

23 y identified type 1 diabetes risk loci: INS, IFIH1, and KIAA0350.

24 are intrinsically less stable than wild-type IFIH1, and lack ATPase activity.

25 egree of concordance on both Ifih1 (+/+) and Ifih1 (-/-) backgrounds, suggesting no substantial contr

26 ons confer gain of function such that mutant IFIH1 binds RNA more avidly, leading to increased baseli

27 fection with ns2(H126R) activated RNase L in Ifih1(-/-) BMM to a similar extent as in wild-type (WT)

28 vitro functional analysis revealed that the IFIH1 c.2465G>A mutation enhanced MDA5 function in inter

29 tion of many immunity genes (including IFNE, IFIH1, cGAS, STING, TLR5, and TLR11), and we suspected t

30 y rescue of the knockdown with nontargetable IFIH1 coding sequence.

31 ncoding either intracellular viral sensors ( IFIH1 , DDX58 , TLR3 , POLR3B , POLR3C ) or other molecu

32 We conclude that IFIH1 deficiency causes a primary immunodeficiency manif

33 icient cardiomyocytes to a similar extent as Ifih1 depletion, identifying IRF7 as the main mediator o

34 In vitro assays showed that IFIH1 effectively restricts replication of human respira

35 hat polymorphic haplotypes in the MDA-5 gene IFIH1 encoding histidine at position 843 and threonine a

36 w-frequency protein-altering variants within IFIH1 (encoding an innate antiviral receptor) and TYK2 (

37 interferon induced with helicase C domain 1 (IFIH1, encoding melanoma differentiation-associated prot

38 th recognized immune functions (IL28RA, REL, IFIH1, ERAP1, TRAF3IP2, NFKBIA and TYK2).

39 onse at the site of autoimmunity, supporting IFIH1 expression as an essential regulator of the diabet

40 Several SNPs outside of the IFIH1 gene also showed significant but weaker associatio

41 aspergillosis patients, polymorphisms in the IFIH1 gene alter the inflammatory response, including IF

42 es demonstrate that mice heterozygous at the Ifih1 gene express less than half the level of MDA5 prot

43 Furthermore, IFIH1 gene expression levels in peripheral blood mononuc

44 Here, we translate the reduction in IFIH1 gene expression that results in protection from T1

45 the 2q region, four SNPs located within the IFIH1 gene or at the 5' region of IFIH1 showed significa

46 rentiation-associated gene 5; encoded by the Ifih1 gene) in Adar1 mutant mice prevented activation of

47 Recent work showed that mutations in the IFIH1 gene, encoding MDA5, lead to interferon-driven aut

48 4) have identified in mice a mutation of the IFIH1 gene, encoding the viral receptor MDA5 that causes

49 lear cells are significantly correlated with IFIH1 genotypes, and higher IFIH1 levels are found in in

50 IFIH1 has been linked to a number of autoimmune disorder

51 interferon induced with helicase C domain 1 (IFIH1) have been identified by genome-wide association s

52 IFIH1 heterozygous mice have a regulatory rather than ef

53 ey-immunity associated genes (TOMM70, ISG15, IFIH1, IFIT2, RPS3, PALS1, NUP98, AXL, ARF6, TRIMM, TRIM

54 This finding firmly establishes the role of IFIH1 in T1D and demonstrates that resequencing studies

55 ent response involved TLR3, NOS2, LITAF, and IFIH1 in the Fayoumi versus IL8, CAMP, and CCL4 in the L

56 yocytes, either alone or in combination with Ifih1 (interferon induced with helicase C domain 1) or I

57 0.74; P = 1.3 x 10(-3) to 2.1 x 10(-16)) in IFIH1 (interferon induced with helicase C domain 1), a g

58 To our knowledge, these results suggest that IFIH1 is a previously unreported psoriasis gene.

59 These results demonstrate that IFIH1 is the innate immune receptor for intron-containin

60 iation and gene expression data suggest that IFIH1 is the most plausible candidate gene implicated in

61 IFN induced with helicase C domain 1 (IFIH1) is a cytoplasmic dsRNA sensor that activates IFN-

62 RNA-Seq showed that IFIH1 knockdown in dendritic cells globally disrupted th

63 correlated with IFIH1 genotypes, and higher IFIH1 levels are found in individuals with the susceptib

64 ciation between T1D and multiple SNPs in the IFIH1 linkage disequilibrium (LD) block on chromosome 2q

65 Since both IFIH1 (MDA5) and DDX58 (RIG-I) signal via MAVS, the spec

66 osphomimetic point mutations, indicates that IFIH1 (MDA5) filament formation, dephosphorylation, and

67 genes tested, only knockdown of XPO1 (CRM1), IFIH1 (MDA5), or MAVS prevented activation of the interf

68 pecific enrichment of unspliced HIV-1 RNA by IFIH1 (MDA5), over two orders of magnitude, was revealed

69 ted to alter the expression and structure of IFIH1 [MDA5 (melanoma differentiation-associated protein

70 LSD1 to silence genes coding for PRRs (TLR3, IFIH1/MDA5, and DDX58/RIG1).

71 Adar1 (E861A/E861A) Ifih1 (-/-) mice are strikingly normal, including their

72 ivation signature in the Adar1 (E861A/E861A) Ifih1 (-/-) mice.

73 xpressing catalytically inactive ADAR1 in an Ifih1-mutant background were completely normal.

74 Our data identify a gain-of-function IFIH1 mutation as causing SMS and leading to early arter

75 Among the top hub genes, MMP2, IL1B, CXCL8, IFIH1, NFKB1A, IL6, ISG15, and EGFR were underexpressed

76 everal of these association signals (IFNLR1, IFIH1, NFKBIA for PsA; TNFRSF9, LCE3C/B, TRAF3IP2, IL23A

77 ered T1D risk (P = 0.007), as exemplified by IFIH1, one of the genes in our IFN signature for which i

78 3)), a region near TYR (P = 1.57 x 10(-13)), IFIH1 (P = 4.91 x 10(-15)), CD80 (P = 3.78 x 10(-10)), C

79 y < 0.01) via gene-wide aggregation testing (IFIH1: pburden = 2.53 x 10-7, OR = 0.707; TYK2: pburden

80 taining RNA from the HIV-1 provirus and that IFIH1 potentially contributes to chronic inflammation in

81 a potential mechanism for patients carrying IFIH1 protective polymorphisms.

82 The importance of IFIH1 protein was demonstrated by rescue of the knockdow

83 We also applied our methods to the IFIH1 region for the type 1 diabetes GWAS data collected

84 (IRF5), prostate cancer and type 1 diabetes (IFIH1 region).

85 ceptibility variants in the IL12B, NOS2, and IFIH1 regions.

86 gle nucleotide polymorphism (SNP) (A946T) in IFIH1, resulted in a gain of function in the MDA5 protei

87 the gene encoding the cytosolic viral sensor IFIH1 results in an amino-acid change (A946T; IFIH1(T946

88 These studies suggest a role for the IFIH1 risk allele in SLE in vivo.

89 We hypothesized that IFIH1 rs199076 variants would modulate host response and

90 impact of the autoimmune-disease-associated IFIH1 rs1990760 (A946T) single nucleotide polymorphism u

91 Thus, the IFIH1 rs1990760 T allele was associated with dsDNA Abs,

92 samples from SLE patients, we found that the IFIH1 rs1990760 T allele was associated with increased I

93 COVID-19 patients with the IFIH1 rs1990760 TT variant show an attenuated inflammato

94 Patients with the IFIH1 rs1990760 TT variant showed a lower expression of

95 association with a nonsynonymous variant in IFIH1 (rs1990760G>A, P = 7.3 x 10(-10)) which was previo

96 ifferentiation-associated gene 5; encoded by IFIH1) sense atypical RNAs associated with virus infecti

97 within the IFIH1 gene or at the 5' region of IFIH1 showed significant association with T1D in the Geo

98 Inhibition of HIV-1-induced ISG15 by the IFIH1-specific Nipah virus V protein, and by IFIH1-trans

99 ied in lupus keratinocytes, including genes (IFIH1, STAT1, and IRF7) encompassed in SLE susceptibilit

100 ings, mice with a knock-in mutation encoding IFIH1(T946) displayed enhanced basal expression of type

101 ) and cell lines expressing the risk variant IFIH1(T946) exhibited heightened basal and ligand-trigge

102 Furthermore, IFIH1(T946) mice manifested an embryonic survival defect

103 FIH1 results in an amino-acid change (A946T; IFIH1(T946)) that is associated with multiple autoimmune

104 ied in her a homozygous missense mutation in IFIH1 that encodes MDA5.

105 Polymorphisms in IFIH1, the gene coding for MDA5, correlate with the risk

106 Common variants of IFIH1, TMEM173 (STING1), and TMEM108 were associated wit

107 roteomic analysis showed increased levels of IFIH1, Tnfaip8l2, IRGM, and IRF5 in mastitis rats, which

108 IFIH1-specific Nipah virus V protein, and by IFIH1-transdominant 2-CARD domain-deletion or phosphomim

109 e genes encoding TLR1-10, NOD1-2, DDX58, and IFIH1 using multiplex assays.

110 5 x 10(-8)) loci and association with a rare IFIH1 variant (p.Ile923Val).

111 S, the specificity of HIV-1 RNA detection by IFIH1 was demonstrated by the fact that DDX58 knockdown

112 the innate immune response such as RSAD2 and IFIH1 were strongly elevated in absence of NRF2 and coin

113 ation associated gene-5 (MDA5, also known as IFIH1), which contain amino-terminal caspase activation

114 ized three rare loss-of-function variants in IFIH1, which encodes an RIG-I-like receptor involved in