Accelerating functional gene discovery in osteoarthritis

Autor: Hannah F. Dewhurst, Peter I. Croucher, Julian A. Waung, Elena J. Ghirardello, Jacqueline K. White, Julia Steinberg, Anne-Tounsia Adoum, J. Mark Wilkinson, Graham R. Williams, Alan Boyde, John G. Logan, Valerie E. Vancollie, Naila S. Mannan, J. H. Duncan Bassett, Fiona Kussy, Natalie C. Butterfield, Davide Komla-Ebri, Lorraine Southam, Antonio C. Bianco, Scott E. Youlten, Victoria D. Leitch, Katherine F. Curry, Christopher J. Lelliott, David J. Adams, Elizabeth A. McAninch, Eleftheria Zeggini, Richard Jacques
Přispěvatelé: Wellcome Trust, Commission of the European Communities, European Commission, Butterfield, Natalie C [0000-0002-5209-7508], Steinberg, Julia [0000-0002-0585-2312], Komla-Ebri, Davide [0000-0002-8381-5381], Leitch, Victoria D [0000-0001-5760-2887], Youlten, Scott E [0000-0001-9314-2945], Wilkinson, J Mark [0000-0001-5577-3674], McAninch, Elizabeth A [0000-0003-3993-4663], Vancollie, Valerie E [0000-0003-1547-1975], Lelliott, Christopher J [0000-0001-8087-4530], Adams, David J [0000-0001-9490-0306], Jacques, Richard [0000-0001-6710-5403], Boyde, Alan [0000-0002-9871-5498], Zeggini, Eleftheria [0000-0003-4238-659X], Croucher, Peter I [0000-0002-7102-2413], Williams, Graham R [0000-0002-8555-8219], Bassett, JH Duncan [0000-0003-0817-0082], Apollo - University of Cambridge Repository
Rok vydání: 2019
Předmět:
musculoskeletal diseases
0301 basic medicine
Science
Mutant
General Physics and Astronomy
Osteoarthritis
Bioinformatics
Iodide Peroxidase
Bone and Bones
General Biochemistry
Genetics and Molecular Biology
Article
Gonadotropin-Releasing Hormone
International Knockout Mouse Consortium
Mice
03 medical and health sciences
0302 clinical medicine
Genome editing
Drug Discovery
medicine
Animals
Paired Box Transcription Factors
CRISPR
Clustered Regularly Interspaced Short Palindromic Repeats
Genetic Predisposition to Disease
Bone
Gene
Genetic Association Studies
030304 developmental biology
Gene Editing
Mice
Knockout
030203 arthritis & rheumatology
0303 health sciences
Multidisciplinary
Drug discovery
Cas9
business.industry
General Chemistry
medicine.disease
Publisher Correction
Phenotype
3. Good health
Disease Models
Animal
030104 developmental biology
Cartilage
CRISPR-Cas Systems
business
Zdroj: Nature Communications
BioRxiv
Nature Communications, Vol 12, Iss 1, Pp 1-18 (2021)
Nat. Commun. 12:467 (2021)
bioRxiv
ISSN: 2041-1723
DOI: 10.1101/836221
Popis: 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.
Osteoarthritis is a chronic, heritable disease with no available treatment. Here, the authors show that a validated, rapid-throughput joint phenotyping pipeline detects osteoarthritis in the mouse knee following surgical provocation, in aging and after single gene deletion or point mutation.
Databáze: OpenAIRE
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