PUBLICATION

A hyperactivating proinflammatory RIPK2 allele associated with early-onset osteoarthritis

Authors
Jurynec, M.J., Sawitzke, A.D., Beals, T.C., Redd, M.J., Stevens, J., Otterud, B., Leppert, M.H., Grunwald, D.J.
ID
ZDB-PUB-180418-56
Date
2018
Source
Human molecular genetics   27(13): 2383-2391 (Journal)
Registered Authors
Grunwald, David, Jurynec, Michael, Redd, Michael
Keywords
none
MeSH Terms
  • Adult
  • Age of Onset
  • Alleles
  • Amino Acid Substitution
  • Animals
  • Chondrocytes/metabolism
  • Chondrocytes/pathology
  • Female
  • Humans
  • Inflammation/genetics*
  • Inflammation/pathology
  • Male
  • NF-kappa B/genetics
  • Osteoarthritis/genetics*
  • Osteoarthritis/pathology
  • Receptor-Interacting Protein Serine-Threonine Kinase 2/genetics*
  • Receptor-Interacting Protein Serine-Threonine Kinases/genetics*
  • Transcription Factor RelA/genetics
  • Whole Exome Sequencing
  • Zebrafish/genetics
  • Zebrafish/growth & development
  • Zebrafish Proteins/genetics*
PubMed
29659823 Full text @ Hum. Mol. Genet.
Abstract
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.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes
This article is corrected by ZDB-PUB-220906-107 .