DOI：10.1038/nature14269 中国科研用户发表 作者：You Li
摘要 : 识别能引起先天性心脏病(CHD)的基因一直具有挑战性，部分是由于将致病性突变同随机序列基因变异区分开来存在困难。
识别能引起先天性心脏病(CHD)的基因一直具有挑战性，部分是由于将致病性突变同随机序列基因变异区分开来存在困难。因此，Cecilia Lo 及同事通过将大规模正向遗传筛选与化学诱变相结合来恢复引起先天性心脏病的突变。他们识别出218个这种疾病的小鼠模型，并用全外显子组测序在61个基因中识别出了91个隐性突变。这些基因当中超过预期数量的一部分基因被发现与纤毛和由纤毛转导的细胞信号作用有关。
Congenital heart disease (CHD) is the most prevalent birth defect, affecting nearly 1% of live births; the incidence of CHD is up to tenfold higher in human fetuses. A genetic contribution is strongly suggested by the association of CHD with chromosome abnormalities and high recurrence risk. Here we report findings from a recessive forward genetic screen in fetal mice, showing that cilia and cilia-transduced cell signalling have important roles in the pathogenesis of CHD. The cilium is an evolutionarily conserved organelle projecting from the cell surface with essential roles in diverse cellular processes. Using echocardiography, we ultrasound scanned 87,355 chemically mutagenized C57BL/6J fetal mice and recovered 218 CHD mouse models. Whole-exome sequencing identified 91 recessive CHD mutations in 61 genes. This included 34 cilia-related genes, 16 genes involved in cilia-transduced cell signalling, and 10 genes regulating vesicular trafficking, a pathway important for ciliogenesis and cell signalling. Surprisingly, many CHD genes encoded interacting proteins, suggesting that an interactome protein network may provide a larger genomic context for CHD pathogenesis. These findings provide novel insights into the potential Mendelian genetic contribution to CHD in the fetal population, a segment of the human population not well studied. We note that the pathways identified show overlap with CHD candidate genes recovered in CHD patients, suggesting that they may have relevance to the more complex genetics of CHD overall. These CHD mouse models and >8,000 incidental mutations have been sperm archived, creating a rich public resource for human disease modelling.
来源： Nature 浏览次数：0