The pituitary tumor-transforming gene 1 (PTTG1) is an oncogene involved in chromosomal segregation, DNA repair, apoptosis, and metabolism. PTTG1 can be used for clinical diagnosis and treatment and is a potential target for oropharyngeal carcinoma. The proliferation and viability of Cal27 and FaDu cells were assessed using the CCK-8 assay. Real-time PCR and western blotting, respectively, were used to analyze the mRNA and protein expression levels of PTTG1 and IFIH1. The interaction between PTTG1 mRNA and the translational regulatory protein IFIH1 was analyzed using RNA pull-down, RNA immunoprecipitation, and luciferase reporter assays. PTTG1 protein was significantly overexpressed in oropharyngeal carcinoma, whereas PTTG1 mRNA was not. We hypothesized that a translation regulatory protein plays a post-transcriptional role in PTTG1. The IFIH1 protein specifically bound to the 42-52 nt region of PTTG1 mRNA, promoted the translation of PTTG1, and promoted the proliferation of oropharyngeal cancer cells. Administration of the PTTG1 inhibitor PHA-848125 and silencing of IFIH1 synergistically decreased the expression of PTTG1, inhibited the proliferation of oropharyngeal cancer cells, and indicated a good prognosis. We found that the IFIH1-PTTG1 axis could regulate the PHA-848125 response and functionally mediate inter-individual oropharyngeal cancer susceptibility and prognosis. This study aimed to confirm the upstream regulatory genes of PTTG1 and further investigate the specific interactions in this signaling pathway, which will provide a new approach for the treatment of oropharyngeal carcinoma.

UNASSIGNED: This study aims to examine whether the genetic variants in the genes for Granzyme B (GZMB) and Interferon Induced with Helicase C domain 1 (IFIH1) were associated with psoriasis.
UNASSIGNED: Psoriasis, a papulosquamous skin disease, was initially thought of as a disorder primarily of epidermal keratinocytes but is now recognized as one of the most common immune-mediated disorders. It is caused by the interplay between multiple genetic and environmental risk factors.
UNASSIGNED: This case-control study has 65 participants with psoriasis and 65 healthy controls. Real-time PCR was used to genotype GZMB (rs8192917) and IFIH1 (rs35667974).
UNASSIGNED: Genotype occurrence and allelic spreading for both SNPs are in Hardy - Weinberg equilibrium. The genotype and allele distributions of rs35667974 showed no differences between the studied groups. Regarding rs8192917, compared to Group II, there is a statistically significant rise in the CC genotype and C allele in Group I. Higher PASI scores are detected in the C/C and C/T genotypes more than the T/T genotype. Univariate and multivariate analyses revealed that BMI, catalase, MDA, and rs8192917 (C/C) are associated with psoriasis.
UNASSIGNED: GZMB rs8192917 was significantly related to psoriasis risk; its C allele is likewise associated with psoriasis vulnerability. However, our investigation found no link between rs35667974 and psoriasis.

Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic islet β-cells are attacked by the immune system, resulting in insulin deficiency and hyperglycemia. One of the top non-synonymous single-nucleotide polymorphisms (SNP) associated with T1D is in the interferon-induced helicase C domain-containing protein 1 (IFIH1), which encodes an anti-viral cytosolic RNA sensor. This SNP results in an alanine to threonine substitution at amino acid 946 (IFIH1A946T) and confers an increased risk for several autoimmune diseases, including T1D. We hypothesized that the IFIH1A946T risk variant, (IFIH1R) would promote T1D pathogenesis by stimulating type I interferon (IFN I) signaling leading to immune cell alterations. To test this, we developed Ifih1R knock-in mice on the non-obese diabetic (NOD) mouse background, a spontaneous T1D model. Our results revealed a modest increase in diabetes incidence and insulitis in Ifih1R compared to non-risk Ifih1 (Ifih1NR) mice and a significant acceleration of diabetes onset in Ifih1R females. Ifih1R mice exhibited a significantly enhanced interferon stimulated gene (ISG) signature compared to Ifih1NR, indicative of increased IFN I signaling. Ifih1R mice exhibited an increased frequency of plasma cells as well as tissue-dependent changes in the frequency and activation of CD8+ T cells. Our results indicate that IFIH1R may contribute to T1D pathogenesis by altering the frequency and activation of immune cells. These findings advance our knowledge on the connection between the rs1990760 variant and T1D. Further, these data are the first to demonstrate effects of Ifih1R in NOD mice, which will be important to consider for the development of therapeutics for T1D.

Type I interferonopathies are a heterogenic group of rare diseases associated with an increase in type I interferon (IFN). The main challenge for the study of Type I interferonopathies is the lack of a well-founded animal model to better characterize the phenotype as well as to perform fast and large drug screenings to offer the best treatment options. In this study, we report the development of a transgenic zebrafish model of Type I interferonopathy overexpressing ifih1 carrying the mutation p.Arg742His (Tg(ifih1_mut)), corresponding to the human mutation p.Arg779His. RNA sequence analysis from Tg(ifih1_mut) larvae revealed a systemic inflammation and IFN signature upon a suboptimal poly I:C induction compared with wild-type larvae, confirming the phenotype observed in patients suffering from Type I interferonopathies. More interestingly, the phenotype was manifested in the zebrafish inflammation and Type I IFN reporters nfkb:eGFP and isg15:eGFP, respectively, making this zebrafish model suitable for future high-throughput chemical screening (HTS). Using the unique advantages of the zebrafish model for gene editing, we have generated Tg(ifih1_mut) knocked down for mavs and ikbke, which completely abrogated the Poly I:C induction and activation of the GFP of the reporters. Finally, we used an FDA-approved drug, Baricitinib (Jak1/Jak2 inhibitor), which was able to reduce the inflammation and the ISG expression. Our results demonstrate the potential of this model to further understand AGS pathological mechanisms and to identify novel therapeutic drugs by HTS.

OBJECTIVE: We aimed to investigate molecular genetic basis of monogenic diabetes (DM) and novel responsible candidate genes with targeted Next Generation Sequencing (NGS) and Whole Exome Sequencing (WES).
METHODS: A hundred cases presenting with clinical findings and a family history of monogenic DM were included in the study. Molecular analysis was performed using an NGS panel including 14 genes. Following targeted NGS, WES was planned in cases in whom no variant was detected.
RESULTS: Thirty different disease-causing variants in seven different genes were detected in thirty-five (35 %) cases with targeted NGS approach. Most common pathogenic variant was found in GCK gene in 25 (25 %) cases. Four different variants were detected in 4 (4 %) patients in ABCC8 gene. In 45 of 65 cases; WES analyses were done. A heterozygous c.2635C > T(p.Gln879Ter) variant was detected in IFIH1 gene in a patient with incidental hyperglycemia. In the segregation analysis affected mother was shown to be heterozygous for the same variant.
CONCLUSIONS: Molecular etiology was determined in 35 % cases with the NGS targeted panel. Seventeen novel variants in monogenic DM genes have been identified. A candidate gene determined by WES analysis in a case that could not be diagnosed with NGS panel in this study.

The melanoma differentiation-associated protein 5 (MDA5; encoded by the IFIH1 gene) mediates the activation of the interferon pathway in response to a viral infection. This protein is also upregulated in autoimmune diseases and psoriasis skin lesions. IFIH1 gene variants that increase MDA5 activity have been associated with an increased risk for immune-mediated diseases, including psoriasis. Our aim is to determine the association between three IFIH1 variants (rs35337543 G/C, intron8 + 1; rs35744605 C/A, Glu627Stop; and rs1990760 C/T, Ala946Thr) and the main clinical findings in a cohort of Spanish patients with psoriasis (N = 572; 77% early-onset). Early-onset psoriasis patients (EOPs) had a significantly higher frequency of severe disease and the Cw6*0602 allele. Carriers of rs1990760 T (946Thr) were more common in the EOPs (p < 0.001), and the effect was more pronounced among Cw6*0602-negatives. This variant was also associated with an increased risk of psoriatic arthritis (PsA) independent from other factors (OR = 1.62, 95%CI = 1.11-2.37). The rs3533754 and rs35744605 polymorphisms did not show significant differences between the two onset age or PsA groups. Compared to the controls, the 946Thr variant was more common in the EOPs (nonsignificant difference) and significantly less common in patients aged >40 years (p = 0.005). In conclusion, the common IFIH1 rs1990760 T allele was significantly more frequent in early-onset compared to late-onset patients. This variant was also an independent risk factor for PsA in our cohort. Our study reinforces the widely reported role of the IFIH1 gene variants on psoriatic disease.

OBJECTIVE: Clinical observations in patients with dermatomyositis (DM) and autoantibodies against the melanoma differentiation-associated protein 5 (MDA5) suggest that the autoantibodies contribute to the pathogenesis of MDA5(+) DM. To gain insight into the role of the anti-MDA5 autoantibodies, we aimed to identify their binding sites on the different domains of the MDA5 protein.
METHODS: We developed an in-house ELISA to assess the reactivity against the MDA5 domains (conformational epitopes) in plasma (n = 8) and serum (n = 24) samples from MDA5(+) patients with varying clinical manifestations and disease outcomes. The reactivities were also assessed using western blot (linearized epitopes). An ELISA-based depletion assay was developed to assess cross-reactivity among the different MDA5 domains.
RESULTS: All eight plasma samples consistently showed reactivity towards conformational and linearized epitopes on the helicase domains of the MDA5 protein. The ELISA-based depletion assay suggests that anti-MDA5 autoantibodies specifically target each of the three helicase domains. Twenty-two of the 24 serum samples showed reactivity in the in-house ELISA and all 22 displayed reactivity towards the helicase domains of the MDA5 protein.
CONCLUSIONS: Our data revealed that the main immunogenic targets of anti-MDA5 autoantibodies from MDA5(+) patients are the helicase domains. Considering that the helicase domains are responsible for the enzymatic activity and subsequent triggering of an inflammatory response, our findings suggest that binding of anti-MDA5 autoantibodies could alter the canonical activity of the MDA5 protein and potentially affect the downstream induction of a pro-inflammatory cascade.

Interferon induced with helicase C domain 1 (IFIH1) single-nucleotide polymorphisms (SNP) rs1990760, rs3747517, and rs10930046 have been shown to be closely related to the risk of autoimmune diseases. The aim of this study was firstly to examine the association of the rs1990760 with type 1 diabetes (T1D) in a Chinese population. Secondly, to assess the association of SNP rs1990760, rs3747517, and rs10930046 with autoimmune diseases susceptibility.
A total of 1,273 T1D patients and 1,010 healthy control subjects in a Chinese population were enrolled in this case-control study. Subsequently, we performed a meta-analysis on the association of the SNP rs1990760, rs3747517, and rs10930046 in the IFIH1 gene with susceptibility to autoimmune diseases. The random and fixed genetic effects models were used to evaluate the association and the effect sizes, including odds ratios (OR) and 95% confidence intervals (CI). Stratification analyses based on ethnicity and the type of autoimmune diseases were performed.
IFIH1 SNP rs1990760 was not associated with a significant risk of T1D in the Chinese population in the case-control study. A total of 35 studies including 70,966 patients and 124,509 controls were identified and included in the meta-analysis. The results displayed significant associations between IFIH1 rs1990760 A allele and rs3747517 C allele and autoimmune diseases risk (OR=1.09, 95% CI: 1.01~1.17; OR=1.24, 95% CI: 1.15~1.25, respectively). Stratified analysis indicated a significant association rs1990760 and rs3747517 with autoimmune diseases risk in the Caucasian population (OR=1.11, 95% CI: 1.02~1.20, OR=1.29, 95% CI: 1.18~1.41, respectively).
This study revealed no association between IFIH1 SNP rs1990760 and T1D in Chinese. Furthermore, the meta-analysis indicated that rs1990760 and rs3747517 polymorphisms, confer susceptibility to autoimmune diseases, especially in the Caucasian population.

BACKGROUND: The IFIH1 gene codes the MDA5 protein and the DDX58 gene codes the RIG-I receptor. Both proteins are parts of the interferon (IFN) I signaling pathway and are responsible for antiviral defense and innate immune response. IFIH1 and DDX58 polymorphisms are associated with a spectrum of autoimmune diseases. Rare gain-of-function IFIH1 mutations have been found in Singleton-Merten and Aicardi-Goutières syndrome, while DDX58 mutation can cause atypical Singleton-Merten syndrome.
OBJECTIVE: To characterize children with pediatric rheumatic diseases (PRD) carrying DDX58 or IFIH1 variants.
METHODS: Clinical exome sequencing was performed on 92 children with different PRD. IFIH1 and DDX58 variants have been detected in 14 children. IFN-I score has been analyzed and the clinical characteristics of patients have been studied.
RESULTS: A total of seven patients with systemic lupus erythematosus (SLE) (n = 2), myelodysplastic syndrome with SLE features at the onset of the disease (n = 1), mixed connective tissue disease (MCTD) (n = 1), undifferentiated systemic autoinflammatory disease (uSAID) (n = 3) have 5 different variants of the DDX58 gene. A common non-pathogenic variant p.D580E has been found in five children. A rare variant of uncertain significance (VUS) p.N354S was found in one patient with uSAID, a rare likely non-pathogenic variant p.E37K in one patient with uSAID, and a rare likely pathogenic variant p.Cys864fs in a patient with SLE. Elevated IFN-I score was detected in 6 of 7 patients with DDX58 variants. Seven patients had six different IFIH1 variants. They were presented with uSAID (n = 2), juvenile dermatomyositis (JDM) (n = 1), SLE-like disease (n = 1), Periodic fever with aphthous stomatitis, pharyngitis, and adenitis syndrome (n = 1), and systemic onset juvenile idiopathic arthritis (n = 1). Three patients have VUS p.E627X, one patient has benign variant p.I923V. Rare VUS p.R595H was detected in the JDM patient. Another rare VUS p.L679Ifs*2 and previously not reported variant p.V599Ffs*5 were detected in the patient with uSAID. One patient with uSAID has rare VUS p.T520A. All patients had elevated IFN-I scores.
CONCLUSIONS: Rare compound-heterozygous IFIH1 variant (p.L679Ifs*2 and p.V599Ffs*5), heterozygous IFIH1 variant (p.T520A) and heterozygous DDX58 variant (p.Cys864fs) are probably disease causative for uSAID and SLE. The majority of patients with different DDX58 and IFI1 variants had hyperactivation of the IFN I signaling pathway.

Hepatitis C remains a major public health problem in the world. The host immune system plays a key role in viral clearance. This study aimed to investigate the connection between retinoic acid-inducible gene I-like (RIG-I-like) receptor gene polymorphism and hepatitis C chronicity in the Chinese Han population. The current study genotyped three SNPs (IFIH1 rs10930046 and DHX58 rs2074158, rs2074160) to assess their association with the chronicity of hepatitis C virus (HCV) infection among 1,590 participants (590 spontaneous HCV clearance cases and 1,000 persistent infection patients). Our research shows that DHX58 rs2074158-G allele (dominant model: adjusted OR = 1.53, 95% CI [1.20-1.95], P = 0.001; additive model: adjusted OR = 1.50, 95% CI [1.27-1.78], P < 0.001) and IFIH1 rs10930046-C allele (additive model: adjusted OR = 1.26, 95% CI [1.07-1.49], P = 0.005) were associated with chronic hepatitis C (CHC). And the risk of CHC increased in people carrying more unfavorable genotypes (rs2074158-AG/GG or rs10930046-CC), with the chronic rates for genotypes number from zero to two in 60.69%, 57.33%, and 85.93%, respectively (adjusted OR = 3.64, 95% CI [2.18-6.08]; P < 0.001). Genetic polymorphism of IFIH1 and DHX58 may be related to CHC in the Chinese Han population. Furthermore, the risk of CHC increases as the number of unfavorable genotypes carried by the HCV-infected person increases. IFIH1 rs10930046, DHX58 rs2074158, age, ALT, and AST levels were all independent predictors of CHC.