Human Disease Phenotypes Associated with Loss and Gain of Function Mutations in STAT2: Viral Susceptibility and Type I Interferonopathy

STAT2 is distinguished from other STAT family members by its exclusive involvement in type I and III interferon (IFN-I/III) signaling pathways, and its unique behavior as both positive and negative regulator of IFN-I signaling. The clinical relevance of these opposing STAT2 functions is exemplified by monogenic diseases of STAT2. Autosomal recessive STAT2 deficiency results in heightened susceptibility to severe and/or recurrent viral disease, whereas homozygous missense substitution of the STAT2-R148 residue is associated with severe type I interferonopathy due to loss of STAT2 negative regulation. Here we review the clinical presentation, pathogenesis, and management of these disorders of STAT2.

Automated summary

STAT2 is unique among the STAT family members in its involvement exclusively in type I and III interferon signaling pathways, acting as both a positive and negative regulator of IFN-I signaling. Opposing functions of STAT2 in monogenic diseases are evident, with autosomal recessive STAT2 deficiency leading to heightened susceptibility to severe viral diseases and homozygous missense substitutions causing severe type I interferonopathy.