IFIH1 Gene: MDA5 and Its Role in Innate Immunity and Autoimmune Disease
Comprehensive guide to IFIH1 (MDA5): genomic information, expression, mutations, and clinical significance.
Gene Information Card
| Symbol | IFIH1 |
|---|---|
| Full Name | Interferon Induced With Helicase C Domain 1 |
| Gene Type | Protein coding |
| Chromosomal Location | 2q24.2 |
| NCBI Gene ID | 64135 ncbi.nlm.nih.gov/gene/64135 |
| Ensembl ID | ENSG00000115267 |
| UniProt ID | Q9BYX4 |
| OMIM ID | 606951 |
| HGNC ID | 18873 |
| Aliases | MDA5, AGS7, IDDM19, SGMRT1, RIG-1-like receptor 2 (RLR-2) |
Description
The IFIH1 gene encodes melanoma differentiation-associated protein 5 (MDA5), a cytosolic pattern recognition receptor that detects double-stranded RNA (dsRNA) from viruses. Upon binding viral RNA, MDA5 activates the MAVS signaling pathway, leading to the production of type I interferons and pro-inflammatory cytokines, crucial for antiviral innate immunity. Mutations in IFIH1 are associated with autoimmune and autoinflammatory diseases, including Aicardi-Goutières syndrome and Singleton-Merten syndrome, as well as susceptibility to type 1 diabetes and systemic lupus erythematosus.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Aicardi-Goutières syndrome 7 (AGS7) | Gain-of-function mutations in IFIH1 lead to constitutive activation of MDA5, causing inappropriate type I interferon production and autoinflammation. | OMIM #615846; ClinVar |
| Singleton-Merten syndrome 1 (SGMRT1) | Gain-of-function mutations (e.g., p.Arg720Gln) enhance MDA5 signaling, leading to abnormal calcification of aorta and teeth, and muscle weakness. | OMIM #182250; ClinVar |
| Type 1 diabetes mellitus (IDDM19) | Loss-of-function variants (e.g., rs1990760) reduce MDA5 activity, impairing viral RNA sensing and altering interferon response, increasing autoimmune risk. | OMIM #601942; GWAS studies |
| Systemic lupus erythematosus (SLE) | IFIH1 variants (e.g., rs1990760) are associated with increased SLE susceptibility, possibly via altered interferon signaling. | ClinVar; PMID 21983784 |
| Inherited susceptibility to viral infections | Loss-of-function mutations impair MDA5-mediated viral recognition, leading to severe respiratory infections (e.g., rhinovirus). | PMID 28559417 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Lung | 9.8 | Medium |
| Spleen | 8.5 | Medium |
| Small intestine | 7.2 | Low |
| Liver | 6.1 | Low |
| Brain | 3.4 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HeLa (cervical cancer) | 12.5 | High expression; used in studies of MDA5 signaling |
| A549 (lung carcinoma) | 10.2 | High; relevant to viral response |
| HepG2 (liver cancer) | 7.8 | Moderate |
| MCF7 (breast cancer) | 5.3 | Low |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| p.Arg720Gln (c.2159G>A) | Missense | Rare (found in Singleton-Merten syndrome) | Gain-of-function; enhances MDA5 signaling, leading to autoinflammation |
| p.Arg779His (c.2336G>A) | Missense | Rare (AGS7) | Gain-of-function; constitutive activation |
| p.Arg843His (c.2528G>A) | Missense | Rare (AGS7) | Gain-of-function; increased interferon response |
| rs1990760 (p.Ala946Thr) | Missense | Common (allele frequency ~30-40%) | Loss-of-function; reduced antiviral response, associated with T1D and SLE |
Mutation functional classification
Loss of Function (LOF)
Loss-of-function mutations (e.g., rs1990760) reduce MDA5's ability to bind viral RNA or activate downstream signaling, leading to impaired type I interferon production and increased susceptibility to viral infections and autoimmune diseases like type 1 diabetes.
Gain of Function (GOF)
Gain-of-function mutations (e.g., p.Arg720Gln, p.Arg779His) cause constitutive activation of MDA5, leading to persistent interferon signaling and autoinflammatory diseases such as Aicardi-Goutières syndrome and Singleton-Merten syndrome.
Dominant Negative (DN)
Some mutations may act in a dominant-negative manner, interfering with wild-type MDA5 function, but specific examples are not well characterized in the literature.
View complete mutation data：
Gene Ontology (GO)
| • RNA helicase activity | • double-stranded RNA binding |
| • ATP binding | • zinc ion binding |
| • innate immune response | • defense response to virus |
| • type I interferon signaling pathway | • apoptotic process |
Pathways
• RIG-I-like receptor signaling pathway (KEGG: hsa04622)
• Cytosolic DNA-sensing pathway (KEGG: hsa04623)
• Innate Immune System (Reactome: R-HSA-168249)
• Interferon Signaling (Reactome: R-HSA-913531)
Protein Summary
MDA5 (IFIH1) is a 1025-amino acid protein containing two N-terminal CARD domains, a central DExD/H-box helicase domain, and a C-terminal regulatory domain. It localizes to the cytoplasm and recognizes long dsRNA (e.g., viral replicative intermediates). Upon binding, it oligomerizes and interacts with MAVS on mitochondria, activating IRF3/7 and NF-κB, leading to type I interferon production. MDA5 also plays a role in detecting picornaviruses and certain synthetic dsRNA analogs like poly(I:C). Its activity is regulated by post-translational modifications and interactions with regulatory proteins.
Related Services
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| IFIH1 Knockout HEK293 Cell Line | EDJ-KQ3770 | Human | 64135 | Details Get a Quote |
| IFIH1 Knockout A-549 Cell Line | EDJ-KQ24494 | Human | 64135 | Details Get a Quote |
| IFIH1 Knockout HCT 116 Cell Line | EDJ-KQ25857 | Human | 64135 | Details Get a Quote |
| IFIH1 Knockout HeLa Cell Line | EDJ-KQ25858 | Human | 64135 | Details Get a Quote |
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