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

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

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

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

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

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

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

12 as three novel secondary associations within IFIH1 and IL12B.

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

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

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

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

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

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

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

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

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

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

23 We conclude that IFIH1 deficiency causes a primary immunodeficiency manif

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

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

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

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

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

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

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

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

32 Furthermore, IFIH1 gene expression levels in peripheral blood mononuc

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

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

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

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

37 IFIH1 has been linked to a number of autoimmune disorder

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

39 IFIH1 heterozygous mice have a regulatory rather than ef

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

41 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

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

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

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

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

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

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

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

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

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

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

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

53 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

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

55 a potential mechanism for patients carrying IFIH1 protective polymorphisms.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

73 5 x 10(-8)) loci and association with a rare IFIH1 variant (p.Ile923Val).

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

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