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Butterfield, N.C.* ; Curry, K.F.* ; Steinberg, J. ; Dewhurst, H.* ; Komla-Ebri, D.* ; Mannan, N.S.* ; Adoum, A.T.* ; Leitch, V.D.* ; Logan, J.G.* ; Waung, J.A.* ; Ghirardello, E.* ; Southam, L. ; Youlten, S.E.* ; Wilkinson, J.M.* ; McAninch, E.A.* ; Vancollie, V.E.* ; Kussy, F.* ; White, J.K.* ; Lelliott, C.J.* ; Adams, D.J.* ; Jacques, R.* ; Bianco, A.C.* ; Boyde, A.* ; Zeggini, E. ; Croucher, P.I.* ; Williams, G.R.* ; Bassett, J.H.D.*

Accelerating functional gene discovery in osteoarthritis.

Nat. Commun. 12:467 (2021)
Publ. Version/Full Text DOI
Open Access Gold
Creative Commons Lizenzvertrag
Osteoarthritis causes debilitating pain and disability, resulting in a considerable socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in randomly selected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we phenotype previously generated mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by CRISPR/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. We hope this expanding resource of mutant mice will accelerate functional gene discovery in osteoarthritis and offer drug discovery opportunities for this common, incapacitating chronic disease.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Mouse Articular-cartilage; Genome-wide Association; Activated Receptor 2; Susceptibility Locus; Transcription Factor; Wnt/beta-catenin; Expression; Differentiation; Identification; Pitx1
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Quellenangaben Volume: 12, Issue: 1, Pages: , Article Number: 467 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed
Institute(s) Institute of Translational Genomics (ITG)
Ernest Heine Family Foundation
European Commission
Wellcome Trust