Genetics and Genomic Medicine Programme, UCL Institute of Child Health, London, WC1N 1EH, UK.
Developmental Biology and Cancer Programme, UCL Institute of Child Health, London, WC1N 1EH, UK.
Sci Rep. 2023 Apr 26;13(1):6783. doi: 10.1038/s41598-023-33589-y.
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.
特发性脊柱侧凸（IS）是指出生后逐渐发展的脊柱变形和/或异常弯曲。这是一种非常常见的病症，大约影响 4%的普通人群，但 IS 的遗传和机制原因尚不清楚。在这里，我们关注 PPP2R3B，它编码一种蛋白磷酸酶 2A 调节亚基。我们发现 PPP2R3B 在人类胎儿的软骨形成部位表达，包括椎骨。我们还在人类胎儿、斑马鱼胚胎和青少年的肌节和肌肉纤维中证明了其显著表达。由于 PPP2R3B 在啮齿动物中没有同源物，我们使用 CRISPR/Cas9 介导的基因编辑在斑马鱼 ppp2r3b 中产生了一系列移码突变。这种突变的纯合青少年斑马鱼表现出完全穿透性的脊柱后凸畸形表型，随着时间的推移逐渐加重，类似于人类的 IS。这些缺陷与椎骨矿化减少有关，类似于骨质疏松症。电子显微镜显示肌肉纤维旁有异常的线粒体。总之，我们报告了一种新的 IS 和骨密度降低的斑马鱼模型。将来，有必要描述这些与骨骼、肌肉、神经元和室管膜纤毛功能相关的缺陷的病因。
