HomozygousSTAT2gain-of-function mutation by loss of USP18 activity in a patient with type I interferonopathy

Abstract

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-offunction (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.

Viral infections in humans and mice with genetic deficiencies of the type I IFN response pathway

“…Excessive inflammation has been reported in four patients as “Kawasaki‐like syndrome” or “HLH‐like syndrome.” Two groups recently reported a homozygous STAT2 missense mutation (R148W/Q) leading to a STAT2 gain of function underlying fatal early‐onset autoinflammation in three patients from two kindreds [147, 148]. The mutation leads to a sustained type I IFN response due to ineffective binding of the mutated STAT2 to ubiquitin specific peptidase 1 (USP18), an essential step in the negative autofeedback loop in which USP18 sterically hinders the binding of JAK1 to IFNAR1 [147]. In conclusion, complete AR STAT2 deficiency typically presents as disseminated LAV infection and recurrent natural viral infections.…”

Shared and Unique Features of Human Interferon-Beta and Interferon-Alpha Subtypes

“…To our knowledge, selective inhibition has been demonstrated by comparing IFNβ induced signaling with that of IFNα2, but not higher affinity IFNAR1 ligands such as IFNα6 or -α8, or those with higher IFNAR1 × IFNAR2 K D products such as IFNω or IFNα14 ( Figure 5 ). The critical importance of USP18-mediated inhibition of IFN signaling is exemplified by pseudo-TORCH syndrome, a severely incapacitating or fatal “interferonopathy” in patients deficient in ISG15, USP18, or with a mutation to the STAT2 binding site for USP18 ( 69 , 73 , 74 ).…”

Monogenic autoinflammatory disorders: Conceptual overview, phenotype, and clinical approach

“…86 The recruitment of USP18 to IFNAR2 requires a binding site on STAT2, and severe early-onset interferonopathy arises from STAT2 mutations that disrupt the interaction with USP18. 87,88 JAK inhibition with ruxolitinib led to remarkable improvement in 1 patient with USP18 deficiency. 89…”