Accelerating functional gene discovery in osteoarthritis

Natalie C. Butterfield, Katherine F. Curry, Julia Steinberg, Hannah Dewhurst, Davide Komla-Ebri, Naila S. Mannan, Anne-Tounsia Adoum, Victoria D. Leitch, John G. Logan, Julian A. Waung, Elena Ghirardello, Lorraine Southam, Scott E. Youlten, J. Mark Wilkinson, Elizabeth A. McAninch, Valerie E. Vancollie, Fiona Kussy, Jacqueline K. White, Christopher J. Lelliott, David J. Adams, Richard Jacques, Antonio C. Bianco, Alan Boyde, Eleftheria Zeggini, Peter I. Croucher, Graham R. Williams () and J. H. Duncan Bassett ()
Additional contact information
Natalie C. Butterfield: Imperial College London
Katherine F. Curry: Imperial College London
Julia Steinberg: Helmholtz Zentrum München – German Research Center for Environmental Health
Hannah Dewhurst: Imperial College London
Davide Komla-Ebri: Imperial College London
Naila S. Mannan: Imperial College London
Anne-Tounsia Adoum: Imperial College London
Victoria D. Leitch: Imperial College London
John G. Logan: Imperial College London
Julian A. Waung: Imperial College London
Elena Ghirardello: Imperial College London
Lorraine Southam: Helmholtz Zentrum München – German Research Center for Environmental Health
Scott E. Youlten: University of New South Wales Medicine
J. Mark Wilkinson: University of Sheffield
Elizabeth A. McAninch: Rush University Medical Center
Valerie E. Vancollie: Wellcome Trust Sanger Institute
Fiona Kussy: Wellcome Trust Sanger Institute
Jacqueline K. White: Wellcome Trust Sanger Institute
Christopher J. Lelliott: Wellcome Trust Sanger Institute
David J. Adams: Wellcome Trust Sanger Institute
Richard Jacques: University of Sheffield
Antonio C. Bianco: University of Chicago
Alan Boyde: Queen Mary University of London, Mile End Road
Eleftheria Zeggini: Helmholtz Zentrum München – German Research Center for Environmental Health
Peter I. Croucher: University of New South Wales Medicine
Graham R. Williams: Imperial College London
J. H. Duncan Bassett: Imperial College London

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-020-20761-5

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