FOXJ1基因突变影响纤毛功能导致心脏发育异常的分子机制

先天性心脏病（CHD）是我国第一大出生缺陷，左右不对称发育信号途径的异常可导致CHD。我们前期在1例复杂CHD家系中发现FOXJ1基因p.L377fs杂合突变，进一步研究证明该突变影响了FOXJ1的转录活性。FOXJ1是纤毛形成过程中的重要转录因子，而纤毛在机体左右不对称发育中发挥重要作用。我们推测FOXJ1基因突变可能通过影响纤毛的正常结构和功能，造成左右不对称发育信号分子的表达紊乱，从而导致CHD的发生。本项目拟通过FOXJ1p.L377fs突变家系患儿及其父母诱导性多能干细胞模型，研究FOXJ1基因突变对机体纤毛结构和功能的影响；并进一步构建Foxj1p.L377fs突变小鼠，研究Foxj1基因突变对小鼠心脏形态结构和左右不对称发育的影响，揭示FOXJ1基因突变导致CHD的分子机制。本项目研究将为纤毛相关CHD致病机制的阐明提供基础，为心脏发育机制研究提供新的思路。

Congenital heart disease (CHD) is the most frequent cause of birth defect in China, and it can be caused by abnormal left-right asymmetric developmental signal. We identified a FOXJ1 p.L377fs heterozygous mutation in a complex CHD family in our previous study, and our further studies revealed that the mutation affected the activity of FOXJ1. FOXJ1 is an important transcription factor in ciliogenesis. And cilia have been proved to play an important role in development. We suppose that FOXJ1 mutation probably affects the structure and function of cilia, causes disorder of left-right asymmetric developmental signal and finally leads to CHD. This project plans to study the effect of FOXJ1 p.L377fs mutation on the structure and function of human cilia, by inducing iPS cells with the patient and parents of the FOXJ1 mutant family, and further construct Foxj1 p.L377fs mutant mice to investigate the effect of Foxj1 frameshift mutation on mouse heart structure and left-right asymmetric body development, and reveal the mechanism of FOXJ1 mutation causing CHD. This study will provide support to the explanation of cilia-related CHD pathogenesis, and new perspective to heart development mechanism.