DNAH10基因变异在青少年特发性脊柱侧凸发生中的作用及机制研究

青少年特发性脊柱侧凸（AIS）是脊柱三维畸形常见疾病，病因尚不明确，目前认为遗传因素占主导作用。课题组前期通过大样本全外显子测序发现一系列AIS新的候选风险基因。其中纤毛结构蛋白编码基因DNAH10在斑马鱼中敲除导致脊柱侧凸，并伴随有瑞氏纤维形成障碍。瑞氏纤维为脑室/脊髓中央管中受纤毛影响的纤维样结构，在脊柱线性生长中起重要作用。因此，我们推测DNAH10变异可能通过干扰DNAH10与微管蛋白的结合来影响脑室/脊髓中央管上皮细胞表面纤毛结构及功能，阻碍瑞氏纤维形成，导致脊柱侧凸发生。在此基础上，本项目拟扩大人群样本检测AIS患者中DNAH10变异聚集情况；应用细胞模型明确dnah10变异对其蛋白功能以及纤毛结构和功能的影响；应用斑马鱼模型验证dnah10变异的致病性及相应分子机制。最终从细胞和分子两个层面揭示DNAH10变异引起AIS发病的详细机制，为全面阐述AIS发病提供新的理论基础。

Adolescent idiopathic scoliosis (AIS) is a common disease of three-dimensional spinal deformity, the underlying mechanism is not fully understood. However, genetic factors are currently considered to play an important role in the pathogenesis. Our research team determined a series of new AIS candidate risk genes through large samples of whole-exome sequencing. Among the candidate genes, we found that the cilia structural protein-encoding gene, DNAH10, can lead zebrafish into scoliosis by knock out, accompanied by Reissner’s fiber formation failure. Reissner's fiber is a fibrous structure affected by cilia in the central spinal canal and plays an important role in the linear growth of the spine. Therefore, we speculate that DNAH10 mutation may affect the structure and function of cilia on the surface of epithelial cells of the ventricle / central spinal canal by interfering with the binding of DNAH10 and tubulin, hindering the formation of Reissner's fibers and causing scoliosis. Based on this theory, we plan to perform MIP sequencing in an expanded AIS sample cohort to detect and verify the DNAH10 variant. We use cell models to clarify the impact of dnah10 mutation on its protein function and cilia structure and function. We use the zebrafish model to verify the pathogenicity of dnah10 mutation and the underlying molecular mechanism. Eventually, our research could reveal the detailed mechanism of DNAH10 mutation in AIS, which provides a new theoretical basis for the comprehensive description of the pathogenesis of AIS.