A hyperactivating proinflammatory RIPK2 allele associated with early-onset osteoarthritis
- Jurynec, M.J., Sawitzke, A.D., Beals, T.C., Redd, M.J., Stevens, J., Otterud, B., Leppert, M.H., Grunwald, D.J.
- Human molecular genetics 27(13): 2383-2391 (Journal)
- Registered Authors
- Grunwald, David, Jurynec, Michael, Redd, Michael
- MeSH Terms
- Age of Onset
- Amino Acid Substitution
- Exome Sequencing
- NF-kappa B/genetics
- Receptor-Interacting Protein Serine-Threonine Kinase 2/genetics*
- Receptor-Interacting Protein Serine-Threonine Kinases/genetics*
- Transcription Factor RelA/genetics
- Zebrafish/growth & development
- Zebrafish Proteins/genetics*
- 29659823 Full text @ Hum. Mol. Genet.
Jurynec, M.J., Sawitzke, A.D., Beals, T.C., Redd, M.J., Stevens, J., Otterud, B., Leppert, M.H., Grunwald, D.J. (2018) A hyperactivating proinflammatory RIPK2 allele associated with early-onset osteoarthritis. Human molecular genetics. 27(13):2383-2391.
Osteoarthritis (OA) is a common debilitating disease characterized by abnormal remodeling of the cartilage and bone of the articular joint. Ameliorating therapeutics are lacking due to limited understanding of the molecular pathways affecting disease initiation and progression. Notably, although a link between inflammation and overt OA is well established, the role of inflammation as a driver of disease occurrence is highly disputed. We analyzed a family with dominant inheritance of early-onset OA and found that affected individuals harbored a rare variant allele encoding a significant amino acid change (p.Asn104Asp) in the kinase domain of Receptor Interacting Protein Kinase 2 (RIPK2), which transduces signals from activated bacterial peptidoglycan sensors through the NF-κB pathway to generate a proinflammatory immune response. Functional analyses of RIPK2 activity in zebrafish embryos indicated the variant RIPK2104Asp protein is hyperactive in its signaling capacity, with augmented ability to activate the innate immune response and the NF-κB pathway and to promote upregulation of OA-associated genes. Further we show a second allele of RIPK2 linked to an inflammatory disease associated with arthritis also has enhanced activity stimulating the NF-κB pathway. Our studies reveal for the first time the inflammatory response can function as a gatekeeper risk factor for OA.
Errata / NotesThis article is corrected by ZDB-PUB-220906-107 .
Genes / Markers
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes