Pediatric Genomics Discovery Program, Department of Pediatrics and Genetics, Yale University School of Medicine, New Haven, CT, United States.
Pediatric Genomics Discovery Program, Department of Pediatrics and Genetics, Yale University School of Medicine, New Haven, CT, United States.
Curr Top Dev Biol. 2021;145:277-312. doi: 10.1016/bs.ctdb.2021.03.005. Epub 2021 Apr 23.
Congenital birth defects result from an abnormal development of an embryo and have detrimental effects on children's health. Specifically, congenital heart malformations are a leading cause of death among pediatric patients and often require surgical interventions within the first year of life. Increased efforts to navigate the human genome provide an opportunity to discover multiple candidate genes in patients suffering from birth defects. These efforts, however, fail to provide an explanation regarding the mechanisms of disease pathogenesis and emphasize the need for an efficient platform to screen candidate genes. Xenopus is a rapid, cost effective, high-throughput vertebrate organism to model the mechanisms behind human disease. This review provides numerous examples describing the successful use of Xenopus to investigate the contribution of patient mutations to complex phenotypes including congenital heart disease and heterotaxy. Moreover, we describe a variety of unique methods that allow us to rapidly recapitulate patients' phenotypes in frogs: gene knockout and knockdown strategies, the use of fate maps for targeted manipulations, and novel imaging modalities. The combination of patient genomics data and the functional studies in Xenopus will provide necessary answers to the patients suffering from birth defects. Furthermore, it will allow for the development of better diagnostic methods to ensure early detection and intervention. Finally, with better understanding of disease pathogenesis, new treatment methods can be tailored specifically to address patient's phenotype and genotype.
先天性出生缺陷是胚胎发育异常引起的，对儿童健康有不良影响。具体来说，先天性心脏畸形是儿科患者死亡的主要原因，通常需要在生命的第一年进行手术干预。人类基因组导航的努力增加了发现患有出生缺陷的患者的多个候选基因的机会。然而，这些努力未能提供关于疾病发病机制的机制的解释，并强调需要有效的候选基因筛选平台。非洲爪蟾是一种快速、具有成本效益的高通量脊椎动物，可用于模拟人类疾病背后的机制。这篇综述提供了许多例子，描述了非洲爪蟾成功地用于研究患者突变对包括先天性心脏病和异位在内的复杂表型的贡献。此外，我们描述了多种独特的方法，使我们能够在青蛙中快速重现患者的表型：基因敲除和敲低策略、用于靶向操作的命运图谱以及新的成像方式。将患者基因组学数据与非洲爪蟾的功能研究相结合，将为患有出生缺陷的患者提供必要的答案。此外，它将允许开发更好的诊断方法，以确保早期发现和干预。最后，通过更好地了解疾病发病机制，可以专门针对患者的表型和基因型制定新的治疗方法。
