Novel mutations of AXIN2 identified in a Chinese Congenital Heart Disease Cohort
Novel mutations of AXIN2 identified in a Chinese Congenital Heart Disease Cohort
复制标题
在中国先天性心脏病队列中发现的 AXIN2 新突变
DOI：
10.1038/s10038-019-0572-x
复制
发表时间：
2019
影响因子：
3.5
通讯作者：
Chen Fengshan
中科院分区：
文献类型：
--
作者：
Zhu Mengjiao;Ma Xiaoyun;Ding Peicheng;Tang Hanfei;Peng Rui;Lu Lei;Li Peiqiang;Qiao Bin;Yang Xueyan;Zheng Yufang;Wang Hongyan;Gao Yunqian;Chen Fengshan
先天性心脏病是人类最常见的先天性出生缺陷，涉及复杂的遗传因素。Wnt/β-catenin通路是心脏发生的关键通路，与许多先天性心脏病的发生密切相关。AXIN 2在Wnt/β-catenin通路中具有独特的作用，它不仅是Wnt/β-catenin通路的重要抑制剂，而且是Wnt/β-catenin通路的直接靶点。然而，AXIN 2是否与人类CHD相关尚未报道。在本研究中，我们发现Axin 2 mRNA在小鼠心脏发育过程中的差异表达，表明其在小鼠心脏发育中的重要性。然后使用靶向的下一代测序，我们在AXIN 2的测序区域中发现了两个新的病例特异性罕见突变[c.28 C > T（p.L10F），c.395 A > G（p.K132R）]。体外功能分析提示L10 F可能是功能丧失型突变，K132 R可能是功能获得型突变。这两种突变均破坏了Wnt/β-catenin通路，未能挽救Axin 2敲低引起的斑马鱼CHD表型。总之，我们的研究表明，AXIN 2的罕见突变可能有助于人类CHD的风险，平衡的经典Wnt通路对心脏发育过程至关重要。据我们所知，这是第一个研究与人类CHD相关的AXIN 2突变，为CHD病因学提供了新的见解。
Congenital heart defects (CHDs), the most common congenital human birth anomalies, involves complex genetic factors. Wnt/β-catenin pathway is critical for cardiogenesis and proved to be associated with numerous congenital heart abnormities. AXIN2 has a unique role in Wnt/β-catenin pathway, as it is not only an important inhibitor but also a direct target of Wnt/β-catenin pathway. However, whether AXIN2 is associated with human CHDs has not been reported. In our present study, we found a differential expression ofAxin2mRNA during the development of mouse heart, indicating its importance in mouse cardiac development. Then using targeted next-generation sequencing, we found two novel case-specific rare mutations [c.28 C > T (p.L10F), c.395 A > G (p.K132R)] in the sequencing region ofAXIN2. In vitro functional analysis suggested that L10F might be a loss-of-function mutation and K132R is a gain-of-function mutation. Both mutations disrupted Wnt/β-catenin pathway and failed to rescue CHD phenotype caused byAxin2knockdown in zebrafish model. Collectively, our study indicates that rare mutations inAXIN2might contribute to the risk of human CHDs and a balanced canonical Wnt pathway is critical for cardiac development process. To our knowledge, it is the first study ofAXIN2mutations associated with human CHDs, providing new insights into CHD etiology.