![]() The human type I interferon (IFNα/ß) system is central to host antiviral defenses and is a critical part of innate immunity. Genetic variation in BRD9 could be considered in future studies to understand the infection susceptibility of some individuals. Thus, while no homozygous BRD9 LOF carriers have yet been identified, our results predict that such extremely rare individuals would exhibit a compromised ability to mount a fully protective IFN-mediated antiviral response. In contrast, all 3 truncated BRD9 LOF variants failed to allow exogenous IFN to function efficiently, as evidenced by exacerbated replication of an IFN-sensitive virus and diminished IFN-stimulated gene expression. ![]() As compared to wild-type BRD9, none of the 12 BRD9 missense variants affected the ability of exogenous IFN to limit virus replication. Using a cell-based BRD9 knock-out and reconstitution model system, we functionally assessed 12 rare human BRD9 missense variants predicted to impair protein function, as well as 3 ultra-rare human BRD9 LOF variants that lead to truncated versions of BRD9. Here, we studied the impact of rare human genetic variants in the recently identified contributor to IFN-stimulated gene expression and antiviral activity, bromodomain-containing protein 9 (BRD9). While loss-of-function (LOF) mutations in canonical JAK-STAT signaling genes (such as IFNAR2, TYK2, STAT1, STAT2 and IRF9) have previously been characterized, little is known about the consequences of mutations in other human factors required for IFN signaling. Consequently, genetic disruption of IFN signaling or effector mechanisms is extremely rare, as affected individuals typically suffer life-threatening infections at an early age. The human type I interferon (IFN) system is central to innate immune defense, and is essential to protect individuals against severe viral disease.
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