Bogunovic, D. | bioRxiv Science

bioRxiv2019

Homozygous STAT2 gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy

Type I interferonopathies are monogenic disorders characterized by enhanced Type I interferon (IFN-I) activity. Inherited ISG15 and USP18 deficiencies underlie type I interferonopathies by preventing the regulation of late responses to IFN-I. Specifically, ISG15/USP18 are induced by IFN-I and sterically hinder JAK1 from binding to the IFNAR2 subunit of IFN-I receptor. We report an infant who died of autoinflammation due to a homozygous missense mutation (R148Q) in STAT2. The variant is gain-of-function (GOF) for ISGF3-dependent induction of late but not early response to IFN-I. Surprisingly, the mutation does not enhance the intrinsic transcriptional activity of ISGF3. Rather, the STAT2 R148Q variant is GOF because it fails to appropriately interact with and traffic USP18 to IFNAR2, preventing USP18 from negatively regulating responses to IFN-I. Overall, a STAT2 missense mutation that fails to facilitate USP18-mediated signal termination in the homozygous state underlies a novel genetic etiology of type I interferonopathy.

immunology↗

bioRxiv2019

Complex Autoinflammatory Syndrome Unveils Fundamental Principles of JAK1 Transcriptional and Biochemical Function

Autoinflammatory disease can result from monogenic errors of immunity. We describe herein the first example of a patient with early-onset widespread autoinflammation resulting from a mosaic, heterozygous, gain-of-function mutation (S703I) in JAK1, encoding a kinase essential for signaling downstream of over twenty-five cytokines. By first-of-its-kind custom single-cell RNA sequencing, we examine mosaicism with single cell resolution. We uncover that JAK1 transcription is predominantly restricted to a single allele across different immune cells, introducing the concept of a mutational \"transcriptotype\" that differs from the genotype. Functionally, the S703I mutation not only increased JAK1 kinase activity, but also resulted in transactivation of partnering JAKs, independently of its catalytic domain. Further, S703I JAK1 was not solely hypermorphic for cytokine signaling, but neomorphic as well, as it enabled downstream signaling cascades not canonically mediated by JAK1. Given these results, the patient was treated with tofacitinib, a JAK inhibitor, which led to rapid resolution of her clinical disease. Together, these findings represent an unprecedented degree of personalized medicine with the concurrent discovery of fundamental biological principles.

immunology↗