IFIH1

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.

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.

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.