Wang Lianlei, Yang Xinyu, Zhao Sen, Zheng Pengfei, Wen Wen, Xu Kexin, Cheng Xi, Li Qing, Khanshour Anas M, Koike Yoshinao, Liu Junjun, Fan Xin, Otomo Nao, Chen Zefu, Li Yaqi, Li Lulu, Xie Haibo, Zhu Panpan, Li Xiaoxin, Niu Yuchen, Wang Shengru, Liu Sen, Yuan Suomao, Terao Chikashi, Li Ziquan, Chen Shaoke, Zhao Xiuli, Liu Pengfei, Posey Jennifer E, Wu Zhihong, Qiu Guixing, Ikegawa Shiro, Lupski James R, Rios Jonathan J, Wise Carol A, Zhang Jianguo T, Zhao Chengtian, Wu Nan
Department of Orthopedic Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
Beijing Key Laboratory of Big Data Innovation and Application for Skeletal Health Medical Care, Beijing, China.
Elife. 2025 Jul 15;13:RP95324. doi: 10.7554/eLife.95324.
Idiopathic scoliosis (IS) is the most common form of spinal deformity with unclear pathogenesis. In this study, we first reanalyzed the loci associated with IS, drawing upon previous studies. Subsequently, we mapped these loci to candidate genes using either location-based or function-based strategies. To further substantiate our findings, we verified the enrichment of variants within these candidate genes across several large IS cohorts encompassing Chinese, East Asian, and European populations. Consequently, we identified variants in the gene as compelling candidates for IS. To confirm their pathogenicity, we generated zebrafish mutants of . Remarkably, the zebrafish mutants exhibited pronounced scoliosis during later stages of development, effectively recapitulating the IS phenotype. We observed that the mutants displayed defects in left-right coordination during locomotion, which arose from disorganized neural activation in these mutants. Our subsequent experiments indicated that the disruption of the central pattern generator (CPG) network, characterized by abnormal axon guidance of spinal cord interneurons, contributed to the disorganization observed in the mutants. Moreover, when knocked down , the ligand for Epha4a, we observed similar CPG defects and disrupted left-right locomotion. These findings suggested that ephrin B3-Epha4 signaling is vital for the proper functioning of CPGs, and defects in this pathway could lead to scoliosis in zebrafish. Furthermore, we identified two cases of IS in , a downstream molecule in the EPHA4 pathway. Collectively, our data provide compelling evidence that neural patterning impairments and disruptions in CPGs may underlie the pathogenesis of IS.
特发性脊柱侧凸（IS）是最常见的脊柱畸形形式，其发病机制尚不清楚。在本研究中，我们首先借鉴以往研究重新分析了与IS相关的基因座。随后，我们使用基于位置或基于功能的策略将这些基因座映射到候选基因。为了进一步证实我们的发现，我们在包括中国、东亚和欧洲人群的几个大型IS队列中验证了这些候选基因内变异的富集情况。因此，我们确定了该基因中的变异是IS的有力候选因素。为了确认它们的致病性，我们生成了该基因的斑马鱼突变体。值得注意的是，斑马鱼突变体在发育后期表现出明显的脊柱侧凸，有效地重现了IS表型。我们观察到突变体在运动过程中左右协调出现缺陷，这是由这些突变体中神经激活紊乱引起的。我们随后的实验表明，以脊髓中间神经元轴突导向异常为特征的中枢模式发生器（CPG）网络的破坏导致了突变体中观察到的紊乱。此外，当敲低Epha4a的配体时，我们观察到类似的CPG缺陷和左右运动紊乱。这些发现表明，ephrin B3-Epha4信号对于CPG的正常功能至关重要，该途径的缺陷可能导致斑马鱼脊柱侧凸。此外，我们在EPHA4途径的下游分子中发现了两例IS病例。总的来说，我们的数据提供了令人信服的证据，表明神经模式形成障碍和CPG破坏可能是IS发病机制的基础。
