Genetic and phenotypic spectrum associated with IFIH1 gain‐of‐function

Abstract

IFIH1 gain‐of‐function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi–Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.

The differing pathophysiologies that underlie COVID‐19‐associated perniosis and thrombotic retiform purpura: a case series

“…It has been suggested that these nucleases are involved in removing nucleic acids that accumulate during apoptosis, and when this process fails, an interferon signal is generated that activates the immune system. MXA, the surrogate marker for type I interferon, would be expected to be significantly upregulated in idiopathic/familial perniosis, chilblain lupus and perniosis in the setting of Aicardi–Goutières syndrome 21 …”

Childhood‐Onset Dystonia Attributed to Aicardi‐Goutières Syndrome and Responsive to Deep Brain Stimulation

“…3 Asymmetric clinical presentations and imaging findings have also been reported. 4 Radiologic features classically include leukoencephalopathy, cerebral calcification, and cerebral atrophy; even a single calcified lesion has been described. 5 Interferon has been implicated in the pathogenesis of AGS, and new therapeutic strategies have been proposed, including Janus kinase inhibitors and antiretrovirals.…”

Genome-Wide CRISPR Screening Identifies BRD9 as a Druggable Component of Interferon-Stimulated Gene Expression and Antiviral Activity

“…An important outcome of our study was the observation that small-molecule mediated degradation of BRD9, using dBRD9-A 43,44 , limits IFN-induced expression of certain ISGs in multiple cell-types. This finding could have implications for the consideration of BRD9 as a viable therapeutic target in the treatment of some autoinflammatory interferonopathies 9–17 , particularly under specific circumstances where broad targeting of JAK-mediated signaling may not be appropriate 21,22 . Furthermore, we also note that BRD9 inhibition (or degradation) is an attractive therapeutic aim for the treatment of several cancers 24,44,60 .…”

“…It is essential that the IFN system is tightly regulated at the molecular level to prevent exuberant proinflammatory responses following infection 6–8 . Furthermore, uncontrolled activation of the IFN system caused by loss- or gain- of-function mutations in key regulators of the IFN pathway can be associated with aberrantly high levels of circulating IFNs and/or the constitutive expression of ISGs, leading to a broad range of autoinflammatory disorders known as interferonopathies 9–17 . Proposed treatments for interferonopathies include JAK inhibitors (such as baricitinib 18 , ruxolitinib 19 or tofacitinib 20 ) to limit the signaling action of high levels of constitutively circulating IFN or inappropriate JAK-STAT regulation.…”