Duncan Anna R, Khokha Mustafa K
Department of Pediatrics, Children's Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, United States.
Department of Pediatrics and Genetics, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520, United States.
Semin Cell Dev Biol. 2016 Mar;51:73-9. doi: 10.1016/j.semcdb.2016.02.022. Epub 2016 Feb 22.
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 discovering 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 patients more effectively in the future.
先天性心脏病是出生缺陷的主要原因，每年每1000名新生儿中就有9人受其影响。先天性心脏病的一种特别严重的形式是内脏反位，这是一种左右发育的紊乱。尽管采取了积极的手术治疗，但由于其复杂的先天性心脏病，内脏反位患者的生存率很低，发病率很高。最近对受影响患者的基因分析发现了内脏反位的新候选基因，但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，包括高基因座异质性和很少的第二个等位基因，这使得确定疾病因果关系变得困难。一个有效的前进策略是在高通量人类疾病模型中分析这些候选基因。非洲爪蟾非常适合这些研究。我们展示了多个例子，证明了非洲爪蟾在通过分析候选内脏反位基因（如GALNT11、NEK2和BCOR）发现新生物学方面的能力。这些基因在胚胎中具有多种作用，并使我们对复杂的信号通路和基础发育生物学有了更深入的了解。我们希望，通过对患者进行下一代测序，在非洲爪蟾中对这些候选基因进行机制分析，将使临床医生对患者的病理生理学有更深入的了解，从而实现更精确和个性化的医疗，以便在未来更有效地帮助患者。
