Xenopus as a model organism for birth defects-Congenital heart disease and heterotaxy.
Xenopus as a model organism for birth defects-Congenital heart disease and heterotaxy.
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DOI：
10.1016/j.semcdb.2016.02.022
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发表时间：
2016-03
影响因子：
7.3
通讯作者：
Khokha MK
中科院分区：
文献类型：
--
作者：
Duncan AR;Khokha MK
先天性心脏病是出生缺陷的主要原因，每年影响千分之九的新生儿。先天性心脏病的一种特别严重的形式是异位性，一种左右发育障碍。尽管进行了积极的手术治疗，异位症患者由于其复杂的先天性心脏病，生存率很低，发病率也很高。最近对受影响患者的遗传分析发现了异源性的新候选基因，尽管其潜在机制仍不清楚。在这篇综述中，我们讨论了出生缺陷研究的重要性和挑战，包括高位点异质性和少数第二等位基因，这些使得确定疾病因果关系变得困难。前进的一个强有力的策略是在高通量人类疾病模型中分析这些候选基因。非洲爪蟾是这些研究的理想选择。我们提供了多个例子，通过分析 GALNT11、NEK2 和 BCOR 等候选异位基因，证明非洲爪蟾在发现新生物学方面的能力。这些基因在胚胎中发挥着不同的作用，使人们对复杂的信号通路和基本发育生物学有了更深入的了解。我们希望，通过下一代患者测序对非洲爪蟾中的这些候选基因进行机制分析，将使临床医生更好地了解患者的病理生理学，从而实现更精确和个性化的医疗，从而在未来更有效地帮助他们。
Congenital heart disease is the leading cause of birth defects, affecting 9 out of 1000 newborns each year. A particularly severe form of congenital heart disease is heterotaxy, a disorder of left-right development. Despite aggressive surgical management, patients with heterotaxy have poor survival rates and severe morbidity due to their complex congenital heart disease. Recent genetic analysis of affected patients has found novel candidate genes for heterotaxy although their underlying mechanisms remain unknown. In this review, we discuss the importance and challenges of birth defects research including high locus heterogeneity and few second alleles that make defining disease causality difficult. A powerful strategy moving forward is to analyze these candidate genes in a high-throughput human disease model. Xenopus is ideal for these studies. We present multiple examples demonstrating the power of Xenopus in discovery new biology from the analysis of candidate heterotaxy genes such as GALNT11, NEK2 and BCOR. These genes have diverse roles in embryos and have led to a greater understanding of complex signaling pathways and basic developmental biology. It is our hope that the mechanistic analysis of these candidate genes in Xenopus enabled by next generation sequencing of patients will provide clinicians with a greater understanding of patient pathophysiology allowing more precise and personalized medicine, to help them more effectively in the future.