Rare coding variants in NOX4 link high ROS levels to psoriatic arthritis mutilans
Abstract 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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2024-02-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s44321-024-00035-z |
| _version_ | 1797259107753787392 |
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| author | Sailan Wang Pernilla Nikamo Leena Laasonen Bjorn Gudbjornsson Leif Ejstrup Lars Iversen Ulla Lindqvist Jessica J Alm Jesper Eisfeldt Xiaowei Zheng Sergiu-Bogdan Catrina Fulya Taylan Raquel Vaz Mona Ståhle Isabel Tapia-Paez |
| author_facet | Sailan Wang Pernilla Nikamo Leena Laasonen Bjorn Gudbjornsson Leif Ejstrup Lars Iversen Ulla Lindqvist Jessica J Alm Jesper Eisfeldt Xiaowei Zheng Sergiu-Bogdan Catrina Fulya Taylan Raquel Vaz Mona Ståhle Isabel Tapia-Paez |
| author_sort | Sailan Wang |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-24T23:04:10Z |
| format | Article |
| id | doaj.art-d7a494fdd8c144ae87005d0481ad98df |
| institution | Directory Open Access Journal |
| issn | 1757-4684 |
| language | English |
| last_indexed | 2024-04-24T23:04:10Z |
| publishDate | 2024-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-d7a494fdd8c144ae87005d0481ad98df2024-03-17T12:34:38ZengSpringer NatureEMBO Molecular Medicine1757-46842024-02-0116359661510.1038/s44321-024-00035-zRare coding variants in NOX4 link high ROS levels to psoriatic arthritis mutilansSailan Wang0Pernilla Nikamo1Leena Laasonen2Bjorn Gudbjornsson3Leif Ejstrup4Lars Iversen5Ulla Lindqvist6Jessica J Alm7Jesper Eisfeldt8Xiaowei Zheng9Sergiu-Bogdan Catrina10Fulya Taylan11Raquel Vaz12Mona Ståhle13Isabel Tapia-Paez14Division of Dermatology and Venereology, Department of Medicine, Solna, Karolinska InstitutetDivision of Dermatology and Venereology, Department of Medicine, Solna, Karolinska InstitutetHelsinki Medical Imaging Center, Helsinki University Central HospitalCentre for Rheumatology Research, University Hospital and Faculty of Medicine, University of IcelandDepartment of Rheumatology, Odense University HospitalDepartment of Dermatology, Aarhus University HospitalDepartment of Medical Sciences, Rheumatology, Uppsala UniversityDepartment of Microbiology, Tumor and Cell Biology & National Pandemic Center, Karolinska InstitutetDepartment of Clinical Genetics, Karolinska University HospitalDepartment of Molecular Medicine and Surgery, Karolinska InstitutetDepartment of Molecular Medicine and Surgery, Karolinska InstitutetDepartment of Clinical Genetics, Karolinska University HospitalDepartment of Molecular Medicine and Surgery, Karolinska InstitutetDivision of Dermatology and Venereology, Department of Medicine, Solna, Karolinska InstitutetDivision of Dermatology and Venereology, Department of Medicine, Solna, Karolinska InstitutetAbstract 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.https://doi.org/10.1038/s44321-024-00035-zNADPH Oxidase 4 (NOX4)Psoriatic Arthritis MutilansReactive Oxygen Species (ROS)Hydrogen PeroxideOsteoclast Differentiation |
| spellingShingle | Sailan Wang Pernilla Nikamo Leena Laasonen Bjorn Gudbjornsson Leif Ejstrup Lars Iversen Ulla Lindqvist Jessica J Alm Jesper Eisfeldt Xiaowei Zheng Sergiu-Bogdan Catrina Fulya Taylan Raquel Vaz Mona Ståhle Isabel Tapia-Paez Rare coding variants in NOX4 link high ROS levels to psoriatic arthritis mutilans EMBO Molecular Medicine NADPH Oxidase 4 (NOX4) Psoriatic Arthritis Mutilans Reactive Oxygen Species (ROS) Hydrogen Peroxide Osteoclast Differentiation |
| title | Rare coding variants in NOX4 link high ROS levels to psoriatic arthritis mutilans |
| title_full | Rare coding variants in NOX4 link high ROS levels to psoriatic arthritis mutilans |
| title_fullStr | Rare coding variants in NOX4 link high ROS levels to psoriatic arthritis mutilans |
| title_full_unstemmed | Rare coding variants in NOX4 link high ROS levels to psoriatic arthritis mutilans |
| title_short | Rare coding variants in NOX4 link high ROS levels to psoriatic arthritis mutilans |
| title_sort | rare coding variants in nox4 link high ros levels to psoriatic arthritis mutilans |
| topic | NADPH Oxidase 4 (NOX4) Psoriatic Arthritis Mutilans Reactive Oxygen Species (ROS) Hydrogen Peroxide Osteoclast Differentiation |
| url | https://doi.org/10.1038/s44321-024-00035-z |
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