Seda, M;
Crespo, B;
Corcelli, M;
Osborn, DP;
Jenkins, D;
(2023)
A CRISPR/Cas9-generated mutation in the zebrafish orthologue of PPP2R3B causes idiopathic scoliosis.
Scientific Reports
, 13
(1)
, Article 6783. 10.1038/s41598-023-33589-y.
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A CRISPRCas9-generated mutation in the zebrafish orthologue of PPP2R3B causes idiopathic scoliosis.pdf - Published Version Download (6MB) | Preview |
Abstract
Idiopathic scoliosis (IS) is the deformation and/or abnormal curvature of the spine that develops progressively after birth. It is a very common condition, affecting approximately 4% of the general population, yet the genetic and mechanistic causes of IS are poorly understood. Here, we focus on PPP2R3B, which encodes a protein phosphatase 2A regulatory subunit. We found that PPP2R3B is expressed at sites of chondrogenesis within human foetuses, including the vertebrae. We also demonstrated prominent expression in myotome and muscle fibres in human foetuses, and zebrafish embryos and adolescents. As there is no rodent orthologue of PPP2R3B, we used CRIPSR/Cas9-mediated gene-editing to generate a series of frameshift mutations in zebrafish ppp2r3b. Adolescent zebrafish that were homozygous for this mutation exhibited a fully penetrant kyphoscoliosis phenotype which became progressively worse over time, mirroring IS in humans. These defects were associated with reduced mineralisation of vertebrae, resembling osteoporosis. Electron microscopy demonstrated abnormal mitochondria adjacent to muscle fibres. In summary, we report a novel zebrafish model of IS and reduced bone mineral density. In future, it will be necessary to delineate the aetiology of these defects in relation to bone, muscle, neuronal and ependymal cilia function.
Type: | Article |
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Title: | A CRISPR/Cas9-generated mutation in the zebrafish orthologue of PPP2R3B causes idiopathic scoliosis |
Location: | England |
Open access status: | An open access version is available from UCL Discovery |
DOI: | 10.1038/s41598-023-33589-y |
Publisher version: | https://doi.org/10.1038/s41598-023-33589-y |
Language: | English |
Additional information: | © 2023 Springer Nature Limited. This article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/). |
Keywords: | Animals, Adolescent, Humans, Zebrafish, Scoliosis, CRISPR-Cas Systems, Zebrafish Proteins, Protein Phosphatase 2, Mutation |
UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept |
URI: | https://discovery.ucl.ac.uk/id/eprint/10169461 |
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