中国汉族人群贲门失弛缓症新致病基因FAM129C和KIF26B的发现及其功能研究

Idiopathic esophageal achalasia is a rare disease of unknown etiology. Genetic susceptibility mediated abnormalities in the development of the enteric nervous system (ENS) might play an important role in its pathogenesis as identified using the candidate gene strategy. However, there has been no system study or search for the pathogenic genes of achalasia. As one of the most prominent centers for achalasia diagnosis and treatment, we have established a large tissue bank for the disease. Through whole exome sequencing of 22 family trios (parents-child) and 100 sporadic patients, we identified FAM129C and KIF26B as the new potential pathogenic genes of achalasia for the Chinese Han population. Based on these, we generated the hypothesis that FAM129C and KIF26B predisposes esophageal achalasia by leading to development abnormalities in the ENS. In this study we plan to: ①clarify the express level and histology distribution of FAM129C and KIF26B in achalasia patients; and ② primarily study the molecular mechanism of genetic mutation induced ENS development abnormalities in mutant animals, which will potentially bring fundamental findings for further study on the pathogenesis of esophageal achalasia.

贲门失弛缓症是一种病因不明的罕见病。遗传易感性导致肠神经系统神经元发育障碍可能与其发病相关，但对致病关键基因缺乏全面搜寻和系统研究。课题组是国内最大贲门失弛缓症诊治中心之一，利用已建立的大规模病例库，通过22个trios家系和100个散发病例全外显子组测序，发现FAM129C和KIF26B为新的、中国汉族人群特异的潜在发病易感基因。基于此，我们提出FAM129C和KIF26B基因突变通过引起肠神经系统神经元发育障碍致病。在本课题我们拟：①明确FAM129C和KIF26B在患者中的表达水平及组织学分布；②突变体动物模型中，明确FAM129C和KIF26B突变是否致贲门失弛缓症发病并初步探讨相关机制，由此为进一步揭示FAM129C和KIF26B突变致病的分子机制奠定基础。

贲门失弛缓症是一种病因不明的罕见病。遗传易感性导致肠神经元发育障碍可能与其发病相关。在本项目资助下，课题组建立了大规模中国汉族人群贲门失弛缓症病例库。通过22个trios家系和100例散发病例全外显子组测序，确定了FAM129C和KIF26B为新的、中国汉族人群特有的潜在发病易感基因。构建了FAM129C和KIF26B 基因突变小鼠模型，正在开展突变致病与肠神经系统神经元发育障碍相关性研究。将遗传与免疫相结合，通过单细胞转录组测序，绘制了11例贲门失弛缓症患者和4例正常对照的外周血、食管下段括约肌组织138168个免疫细胞的单细胞图谱。研究结果为阐明贲门失弛缓发病机制提供新的线索和理论依据，并为将治疗由对症转向对因提供潜在靶点。