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URL of this page: https://medlineplus.gov/genetics/gene/ifih1/

IFIH1 gene

interferon induced with helicase C domain 1

Normal Function

The IFIH1 gene provides instructions for making the MDA5 protein, which plays an important role in innate immunity, the body's early, response to foreign invaders (pathogens) such as viruses and bacteria. In particular, the MDA5 protein recognizes a molecule called double-stranded RNA (a chemical cousin of DNA). Certain viruses, including rhinovirus (the virus that causes the common cold), respiratory syncytial virus (RSV), and the influenza (flu) virus, use RNA as their genetic material or produce RNA when they infect cells and copy (replicate) themselves. Another subset of viruses has DNA as their genetic material.

MDA5 proteins attach themselves to pieces of viral RNA inside the cell, forming a filament. This stimulates signals that turn on the production of immune system proteins called interferons. Interferons control the activity of genes that help block viruses from replicating themselves and stimulate the activity of certain immune system cells to fight infection. Interferons also help regulate inflammation, which is another part of the body's innate immune response.

Health Conditions Related to Genetic Changes

Aicardi-Goutières syndrome

Variants (also called mutations) in the IFIH1 gene have been found to cause Aicardi-Goutières syndrome. This disorder is characterized by abnormalities of the immune system, skin, and brain. Some affected individuals have calcium deposits in parts of the brain.

The IFIH1 gene variants involved in Aicardi-Goutières syndrome are described as "gain-of-function" variants because they lead to the production of an MDA5 protein that is more active than usual. The altered protein may more readily attach to RNA, including pieces of RNA that are not from viruses, or to other MDA5 proteins to form filaments. Alternatively, filaments that contain the altered protein may not be broken down when immune signaling is no longer needed. As a result of these changes, the cell produces more interferons than needed, leading to excessive immune system activity and inflammation.

Constant inflammation is thought to disrupt the way calcium is handled in the body. This can create calcium deposits in the brain in some people with Aicardi-Goutières syndrome. Excessive inflammation is also thought to damage cells in the brain and skin, leading to the signs and symptoms of Aicardi-Goutières syndrome.

More About This Health Condition

MDA5 deficiency

A few variants in the IFIH1 gene have been found to cause MDA5 deficiency, an immune system disorder (immunodeficiency) that leads to recurrent, severe viral infections in the lungs and airways (respiratory tract). These infections are most commonly caused by rhinovirus, RSV, and the flu virus. The variants in the IFIH1 gene that cause this condition are described as "loss-of-function" variants because they lead to an altered version of the MDA5 protein that cannot function. Studies suggest that the altered protein is unable to attach to viral RNA or to other MDA5 proteins to form filaments. Without interferons to stimulate the important early immune response, infants with MDA5 deficiency experience severe viral infections.

More About This Health Condition

Other disorders

IFIH1 gene variants have also been found to cause Singleton-Merten syndrome. A feature of Singleton-Merten syndrome is calcium deposits in the large vessel that carries blood from the heart to the rest of the body (the aorta) and in certain valves in the heart. Other signs and symptoms include tooth abnormalities, low bone density (osteopenia), and other bone problems. Some people with IFIH1 gene variants have signs and symptoms of both Singleton-Merten syndrome and Aicardi-Goutières syndrome (described above), suggesting that these two conditions may be part of a spectrum of disorders caused by IFIH1 gene variants.

As in Aicardi-Goutières syndrome, the IFIH1 gene variants involved in Singleton-Merten syndrome are described as "gain-of-function" variants and lead to excessive immune system activity and inflammation, disrupting calcium handling in the body. It is unclear why people with gain-of-function variants in the IFIH1 gene develop the signs and symptoms of one condition or the other.

Singleton-Merten syndrome and Aicardi-Goutières syndrome both have autoimmune features, which occur when the immune system malfunctions and damages the body's own tissues and organs. Common variations (polymorphisms) in the IFIH1 gene have been associated with other autoimmune disorders. It is thought that polymorphisms that enhance the activity of the MDA5 protein increase the risk of certain autoimmune disorders, while polymorphisms that reduce the activity of the MDA5 protein help protect against other autoimmune disorders.

Other Names for This Gene

  • IDDM19
  • interferon-induced helicase C domain-containing protein 1
  • MDA-5
  • MDA5
  • melanoma differentiation-associated gene 5
  • melanoma differentiation-associated protein 5
  • murabutide down-regulated protein
  • RIG-I-like receptor 2
  • RLR-2
  • RNA helicase-DEAD box protein 116

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases

References

  • Asgari S, Schlapbach LJ, Anchisi S, Hammer C, Bartha I, Junier T, Mottet-Osman G, Posfay-Barbe KM, Longchamp D, Stocker M, Cordey S, Kaiser L, Riedel T, Kenna T, Long D, Schibler A, Telenti A, Tapparel C, McLaren PJ, Garcin D, Fellay J. Severe viral respiratory infections in children with IFIH1 loss-of-function mutations. Proc Natl Acad Sci U S A. 2017 Aug 1;114(31):8342-8347. doi: 10.1073/pnas.1704259114. Epub 2017 Jul 17. Citation on PubMed or Free article on PubMed Central
  • Berke IC, Yu X, Modis Y, Egelman EH. MDA5 assembles into a polar helical filament on dsRNA. Proc Natl Acad Sci U S A. 2012 Nov 6;109(45):18437-41. doi: 10.1073/pnas.1212186109. Epub 2012 Oct 22. Citation on PubMed or Free article on PubMed Central
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  • Looney BM, Xia CQ, Concannon P, Ostrov DA, Clare-Salzler MJ. Effects of type 1 diabetes-associated IFIH1 polymorphisms on MDA5 function and expression. Curr Diab Rep. 2015 Nov;15(11):96. doi: 10.1007/s11892-015-0656-8. Citation on PubMed
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  • Rutsch F, MacDougall M, Lu C, Buers I, Mamaeva O, Nitschke Y, Rice GI, Erlandsen H, Kehl HG, Thiele H, Nurnberg P, Hohne W, Crow YJ, Feigenbaum A, Hennekam RC. A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome. Am J Hum Genet. 2015 Feb 5;96(2):275-82. doi: 10.1016/j.ajhg.2014.12.014. Epub 2015 Jan 22. Citation on PubMed or Free article on PubMed Central
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