Molecular Medicine and Medical Biotechnology, Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany.
Hum Mutat. 2010 Nov;31(11):1185-94. doi: 10.1002/humu.21345. Epub 2010 Oct 12.
Congenital heart disease (CHD) is among the most prevalent and fatal of all birth defects. Deciphering its causes, however, is complicated, as many patients affected by CHD have no family history of the disease. There is also widespread heterogeneity of cardiac malformations within affected individuals. Nonetheless, there have been tremendous efforts toward a better understanding of the molecular and cellular events leading to CHD. Notably, certain cardiac-specific transcription factors have been implicated in mammalian heart development and disruption of their activity has been demonstrated in CHD. The homeodomain transcription factor NKX2-5 is an important member of this group. Indeed, more than 40 heterozygous NKX2-5 germline mutations have been observed in individuals with CHD, and these are spread along the coding region, with many shown to impact protein function. Thus, NKX2-5 appears to be hypermutable, yet the overall detection frequency in sporadic CHD is about 2% and NKX2-5 mutations are one-time detections with single-positives or private to families. Furthermore, there is lack of genotype-phenotype correlation, in which the same cardiac malformations have been exhibited in different NKX2-5 mutations or the same NKX2-5 mutation associated with diverse malformations. Here, we summarize published NKX2-5 germline mutations and explore different avenues in disease pathogenesis to support the notion of a multifactorial cause of CHD where possibly several genes and associated pathways are involved.
先天性心脏病（CHD）是所有出生缺陷中最常见和最致命的疾病之一。然而，要了解其病因却很复杂，因为许多患有 CHD 的患者没有家族病史。受影响个体的心脏畸形也存在广泛的异质性。尽管如此，人们还是做出了巨大的努力来更好地理解导致 CHD 的分子和细胞事件。值得注意的是，某些心脏特异性转录因子参与了哺乳动物心脏发育，并且已经证明它们的活性失调与 CHD 有关。同源域转录因子 NKX2-5 是该组的重要成员。事实上，在患有 CHD 的个体中已经观察到超过 40 种杂合性 NKX2-5 种系突变，并且这些突变沿着编码区分布，许多突变影响蛋白功能。因此，NKX2-5 似乎易发生突变，但在散发性 CHD 中的总检出频率约为 2%，并且 NKX2-5 突变是一次性检测，呈单阳性或家族特有。此外，还缺乏基因型-表型相关性，即不同的 NKX2-5 突变表现出相同的心脏畸形，或者相同的 NKX2-5 突变与不同的畸形相关。在这里，我们总结了已发表的 NKX2-5 种系突变，并探讨了疾病发病机制的不同途径，以支持 CHD 多因素病因的观点，其中可能涉及几个基因和相关途径。
