Rare coding variants in NOX4 link high ROS levels to psoriatic arthritis mutilans

Psoriatic arthritis mutilans (PAM) is the rarest and most severe form of psoriatic arthritis, characterized by erosions of the small joints and osteolysis leading to joint disruption. Despite its severity, the underlying mechanisms are unknown, and no susceptibility genes have hitherto been identified. We aimed to investigate the genetic basis of PAM by performing massive parallel sequencing in sixty-one patients from the PAM Nordic cohort. We found rare variants in the NADPH oxidase 4 ( NOX4 ) in four patients. In silico predictions show that the identified variants are potentially damaging. NOXs are the only enzymes producing reactive oxygen species (ROS). NOX4 is specifically involved in the differentiation of osteoclasts, the cells implicated in bone resorption. Functional follow-up studies using cell culture, zebrafish models, and measurement of ROS in patients uncovered that these NOX4 variants increase ROS levels both in vitro and in vivo. We propose NOX4 as the first candidate susceptibility gene for PAM. Our study links high levels of ROS caused by NOX4 variants to the development of PAM, offering a potential therapeutic target. Synopsis Genomic analysis of Psoriatic Arthritis Mutilans (PAM) patients from the Nordic PAM cohort uncovered potentially damaging rare variants in the NOX4 gene. NOX4 belongs to a family of enzymes generating reactive oxygen species (ROS); NOX4 generates mainly hydrogen peroxide (H 2 O 2 ). Three NOX4 rare variants (p.V369F, p.Y512IfsX20, and p.Y512C) affecting NOX4 functional domains were identified in four PAM patients. Enhanced differentiation and higher generation of ROS activity are observed in patient-derived osteoclasts, the cells responsible for bone resorption. NOX4 rare variants show increased generation of ROS in both zebrafish model and HEK293 cells. Increased levels of ROS, particularly H 2 O 2 , present promising therapeutic opportunities for addressing PAM. Genomic analysis of Psoriatic Arthritis Mutilans (PAM) patients from the Nordic PAM cohort uncovered potentially damaging rare variants in the NOX4 gene. NOX4 belongs to a family of enzymes generating reactive oxygen species (ROS); NOX4 generates mainly hydrogen peroxide (H 2 O 2 ).