Mutation of FOXC1 and PITX2 induces cerebral small-vessel disease
Mutation of FOXC1 and PITX2 induces cerebral small-vessel disease
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DOI：
10.1172/jci75109
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发表时间：
2014-11-01
影响因子：
15.9
通讯作者：
Lehmann, Orden J.
中科院分区：
文献类型：
--
作者：
French, Curtis R.;Seshadri, Sudha;Lehmann, Orden J.
脑小血管病（CSVD）患者表现出动脉末端功能紊乱，卒中和年龄相关性认知功能下降的风险增加。在这里，我们使用有针对性的全基因组关联（GWA）分析，并定义了一个CSVD位点附近的叉头转录因子FOXC 1。此外，我们确定了相关的SNPs影响FOXC 1转录水平，并证明了FOXC 1功能改变的1岁患者表现出CSVD。错义和无义突变以及FOXC 1节段性重复和缺失患者的MRI分析显示白色高信号、血管周围间隙扩张和腔隙性梗死。在斑马鱼模型中，foxc 1的过度表达或吗啉代诱导的抑制诱导脑出血。抑制foxc 1扰乱血小板衍生生长因子（Pdgf）信号传导，损害神经嵴迁移和壁细胞的募集，这是血管稳定性所必需的。GWA分析还将FOXC 1相互作用转录因子PITX 2与CSVD联系起来，PITX 2突变患者和小鼠Pitx 2（-/-）突变患者均显示脑血管表型。总之，这些结果扩展了中风的遗传病因学，并证明了人类脑血管疾病的发展基础。
Patients with cerebral small-vessel disease (CSVD) exhibit perturbed end-artery function and have an increased risk for stroke and age-related cognitive decline. Here, we used targeted genome-wide association (GWA) analysis and defined a CSVD locus adjacent to the forkhead transcription factor FOXC1. Moreover, we determined that the linked SNPs influence FOXC1 transcript levels and demonstrated that patients as young as 1 year of age with altered FOXC1 function exhibit CSVD. MRI analysis of patients with missense and nonsense mutations as well as FOXC1-encompassing segmental duplication and deletion revealed white matter hyperintensities, dilated perivascular spaces, and lacunar infarction. In a zebrafish model, overexpression or morpholino-induced suppression of foxc1 induced cerebral hemorrhage. Inhibition of foxc1 perturbed platelet-derived growth factor (Pdgf) signaling, impairing neural crest migration and the recruitment of mural cells, which are essential for vascular stability. GWA analysis also linked the FOXC1-interacting transcription factor PITX2 to CSVD, and both patients with PITX2 mutations and murine Pitx2(-/-) mutants displayed brain vascular phenotypes. Together, these results extend the genetic etiology of stroke and demonstrate an increasing developmental basis for human cerebrovascular disease.