Department of Orthodontics, School and Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai, 200072, China.
Department of Cardiothoracic Surgery, Children's Hospital of Nanjing Medical University, Nanjing, 210008, China.
J Hum Genet. 2019 May;64(5):427-435. doi: 10.1038/s10038-019-0572-x. Epub 2019 Feb 13.
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 of Axin2 mRNA 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 of AXIN2. 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 by Axin2 knockdown in zebrafish model. Collectively, our study indicates that rare mutations in AXIN2 might 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 of AXIN2 mutations associated with human CHDs, providing new insights into CHD etiology.
先天性心脏缺陷（CHD）是最常见的先天性人类出生畸形，涉及复杂的遗传因素。Wnt/β-catenin 通路对心脏发生至关重要，并被证明与许多先天性心脏异常有关。AXIN2 在 Wnt/β-catenin 通路中具有独特的作用，因为它不仅是一个重要的抑制剂，也是 Wnt/β-catenin 通路的直接靶标。然而，AXIN2 是否与人类 CHD 相关尚未有报道。在我们目前的研究中，我们发现 Axin2 mRNA 在小鼠心脏发育过程中存在差异表达，表明其在小鼠心脏发育中的重要性。然后，我们使用靶向下一代测序，在 AXIN2 的测序区域发现了两个新的病例特异性罕见突变[c.28C>T(p.L10F)，c.395A>G(p.K132R)]。体外功能分析表明，L10F 可能是一个失能突变，而 K132R 是一个获得性功能突变。这两种突变均破坏了 Wnt/β-catenin 通路，并且未能挽救 Axin2 敲低在斑马鱼模型中引起的 CHD 表型。总之，我们的研究表明，AXIN2 中的罕见突变可能导致人类 CHD 的风险增加，而平衡的经典 Wnt 通路对心脏发育过程至关重要。据我们所知，这是首例与人类 CHD 相关的 AXIN2 突变研究，为 CHD 的病因学提供了新的见解。
