Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
UCL Great Ormond Street Institute of Child Health, Section Developmental Biology of Birth Defects, London, UK.
Am J Med Genet C Semin Med Genet. 2017 Dec;175(4):487-495. doi: 10.1002/ajmg.c.31590. Epub 2017 Oct 31.
Heart defects caused by loss-of-function mutations in CHD7 are a frequent cause of morbidity and mortality in CHARGE syndrome. Here we review the clinical and molecular aspects of CHD7 that are related to the cardiovascular manifestations of the syndrome. The types of heart defects found in patients with CHD7 mutations are variable, with an overrepresentation of atrioventricular septal defect and outflow tract defect including aortic arch anomalies compared to nonsyndromic heart defects. Chd7 haploinsufficiency in mouse is a good model for studying the heart effects seen in CHARGE syndrome, and mouse models reveal a role for Chd7 in multiple lineages during heart development. Formation of the great vessels requires Chd7 expression in the pharyngeal surface ectoderm, and this expression likely has an non-autonomous effect on neural crest cells. In the cardiogenic mesoderm, Chd7 is required for atrioventricular cushion development and septation of the outflow tract. Emerging knowledge about the function of CHD7 in the heart indicates that it may act in concert with transcription factors such as TBX1 and SMADs to regulate genes such as p53 and the cardiac transcription factor NKX2.5.
CHD7 功能丧失突变导致的心脏缺陷是 CHARGE 综合征发病率和死亡率的一个常见原因。本文综述了与该综合征心血管表现相关的 CHD7 的临床和分子方面。CHD7 突变患者的心脏缺陷类型多种多样，与非综合征性心脏缺陷相比，房室间隔缺损和流出道缺陷（包括主动脉弓异常）更为常见。Chd7 杂合不足的小鼠是研究 CHARGE 综合征心脏效应的良好模型，小鼠模型揭示了 Chd7 在心脏发育的多个谱系中的作用。大血管的形成需要 Chd7 在咽面外胚层中的表达，这种表达可能对神经嵴细胞有非自主作用。在心肌中胚层，Chd7 对于房室间隔垫发育和流出道分隔是必需的。关于 CHD7 在心脏中的功能的新知识表明，它可能与 TBX1 和 SMADs 等转录因子协同作用，调节 p53 和心脏转录因子 NKX2.5 等基因。
