功能筛选先天性心脏病风险基因座，在斑马鱼中鉴定出 5 个心脏发育必需基因。
Functional screening of congenital heart disease risk loci identifies 5 genes essential for heart development in zebrafish.
机构信息
Institute of Developmental Biology and Regenerative Medicine, Southwest University, Chongqing, 400715, China.
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211100, China.
出版信息
Cell Mol Life Sci. 2022 Dec 27;80(1):19. doi: 10.1007/s00018-022-04669-5.
Congenital heart disease (CHD) is the most common birth defect worldwide and a main cause of perinatal and infant mortality. Our previous genome-wide association study identified 53 SNPs that associated with CHD in the Han Chinese population. Here, we performed functional screening of 27 orthologous genes in zebrafish using injection of antisense morpholino oligos. From this screen, 5 genes were identified as essential for heart development, including iqgap2, ptprt, ptpn22, tbck and maml3. Presumptive roles of the novel CHD-related genes include heart chamber formation (iqgap2 and ptprt) and atrioventricular canal formation (ptpn22 and tbck). While deficiency of maml3 led to defective cardiac trabeculation and consequent heart failure in zebrafish embryos. Furthermore, we found that maml3 mutants showed decreased cardiomyocyte proliferation which caused a reduction in cardiac trabeculae due to inhibition of Notch signaling. Together, our study identifies 5 novel CHD-related genes that are essential for heart development in zebrafish and first demonstrates that maml3 is required for Notch signaling in vivo.
先天性心脏病（CHD）是全球最常见的出生缺陷，也是围产期和婴儿死亡的主要原因。我们之前的全基因组关联研究确定了 53 个与汉族人群 CHD 相关的 SNP。在这里，我们使用反义 morpholino 寡核苷酸注射在斑马鱼中对 27 个直系同源基因进行了功能筛选。从该筛选中，鉴定出 5 个对心脏发育至关重要的基因，包括 iqgap2、ptprt、ptpn22、tbck 和 maml3。这些新的与 CHD 相关的基因的推测作用包括心腔形成（iqgap2 和 ptprt）和房室管形成（ptpn22 和 tbck）。而 maml3 的缺乏导致斑马鱼胚胎中心律不齐和心力衰竭。此外，我们发现 maml3 突变体表现出心肌细胞增殖减少，这导致由于 Notch 信号抑制而导致心内膜小梁减少。总之，我们的研究确定了 5 个在斑马鱼心脏发育中必不可少的新的 CHD 相关基因，并首次证明 maml3 在体内 Notch 信号传导中是必需的。
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