Clinical case of type I interferonopathy: homozygous STAT2 gain-of-function mutation

Abstract

The article is devoted to an extremely rare variant of type I interferonopathies associated with a homozygous gain of function (GOF) mutation in the STAT2 gene in a 5-year-old child. This genetic defect was first described in 2019, and so far only 3 cases are known in the world with a similar pathology. Here we present the fourth clinical case and our experience in managing a patient with STAT2 GOF. The article presents the key aspects of the pathogenesis, clinical picture based on the analysis of all known cases of the disease. The absence of established criteria and methods of treatment for this disease is due to the rarity and relative novelty of the described nosology. We present the experience of treatment using a JAK kinase inhibitor, followed by an assessment of the effectiveness of the therapy and side effects. The patient's parents agreed to use the information, including the child's photo, in scientific research and publications.

A partial form of inherited human USP18 deficiency underlies infection and inflammation

“…5 A ). In this scenario, we wanted to test why the high IFN-I levels in patients with other type I interferonopathies do not cause MSMD (i.e., AGS1-7), with the exception of ISG15 deficiency and recessive STAT2 GOF mutations ( Bogunovic et al, 2012 ; Gruber et al, 2020a ; Kozlova et al, 2021 ). To explain this, we tested TREX KO THP1 cells.…”

“…STAT2 was recently discovered to recruit USP18 to IFNAR2, where USP18 exerts its negative regulatory function ( Arimoto et al, 2017 ). Patients with STAT2 GOF mutations clinically phenocopy USP18 deficiency owing to impaired STAT2-mediated recruitment of USP18 to IFNAR2 (R148Q) or improper interaction of STAT2 with USP18 (R148W; Gruber et al, 2020a ; Duncan et al, 2019 ; Kozlova et al, 2021 ). Preliminary in silico prediction analyses suggest that the I60N variant may affect bond strength, possibly decreasing the flexibility of the protein and the interaction with STAT2.…”

“…In recent years, an increasing number of genetic disorders presenting with perturbations in the regulation of IFN-I responses have been discovered and included in the larger type I interferonopathy family ( Tangye et al, 2020 ). These include proteasome associated autoinflammatory syndromes ( Ohmura, 2019 ; Torrelo et al, 2010 ), Singleton-Merten syndrome and its atypical presentation ( Jang et al, 2015 ; Rutsch et al, 2015 ; Pettersson et al, 2017 ), stimulator of IFN genes–associated vasculopathy with onset in infancy ( Liu et al, 2014 ), STAT1 gain-of-function (GOF; Liu et al, 2011 ; Toubiana et al, 2016 ), JAK1 GOF ( Gruber et al, 2020b ), STAT2 GOF ( Gruber et al, 2020a ; Duncan et al, 2019 ; Kozlova et al, 2021 ), ISG15 deficiency ( Bogunovic et al, 2012 ; Zhang et al, 2015 ; Hermann and Bogunovic, 2017 ; Martin-Fernandez et al, 2020 ), and ubiquitin-specific peptidase 18 (USP18) complete deficiency, presenting as pseudo-TORCH (toxoplasmosis, other [syphilis, varicella, mumps, parvovirus and HIV], rubella, cytomegalovirus, and herpes simplex) syndrome ( Meuwissen et al, 2016 ; Alsohime et al, 2020 ).…”

“…, stimulator of IFN genes-associated vasculopathy with onset in infancy (Liu et al, 2014), STAT1 gain-offunction (GOF; Liu et al, 2011;Toubiana et al, 2016), JAK1 GOF (Gruber et al, 2020b), STAT2 GOF (Gruber et al, 2020a;Duncan et al, 2019;Kozlova et al, 2021), ISG15 deficiency (Bogunovic et al, 2012;Zhang et al, 2015;Hermann and Bogunovic, 2017;Martin-Fernandez et al, 2020), and ubiquitin-specific peptidase 18 (USP18) complete deficiency, presenting as pseudo-TORCH (toxoplasmosis, other [syphilis, varicella, mumps, parvovirus and HIV], rubella, cytomegalovirus, and herpes simplex) syndrome (Meuwissen et al, 2016;.…”