Abstract：
Cerebral small vessel disease (CSVD) is a prominent cause of ischemic and hemorrhagic stroke and a leading cause of vascular dementia, affecting small penetrating vessels of the brain. Despite current advances in genetic susceptibility studies, challenges remain in defining the causative genes and the underlying pathophysiological mechanisms. Here, we reported that the ARHGEF15 gene was a causal gene linked to autosomal dominant inherited CSVD. We identified one heterozygous nonsynonymous mutation of the ARHGEF15 gene that cosegregated completely in two families with CSVD, and a heterozygous nonsynonymous mutation and a stop-gain mutation in two individuals with sporadic CSVD, respectively. Intriguingly, clinical imaging and pathological findings displayed severe osteoporosis and even osteoporotic fractures in all the ARHGEF15 mutation carriers. In vitro experiments indicated that ARHGEF15 mutations resulted in RhoA/ROCK2 inactivation-induced F-actin cytoskeleton disorganization in vascular smooth muscle cells and endothelial cells and osteoblast dysfunction by inhibiting the Wnt/β-catenin signaling pathway in osteoblast cells. Furthermore, Arhgef15-e(V368M)1 transgenic mice developed CSVD-like pathological and behavioral phenotypes, accompanied by severe osteoporosis. Taken together, our findings provide strong evidence that loss-of-function mutations of the ARHGEF15 gene cause CSVD accompanied by osteoporotic fracture.
摘要：
脑小血管病（CSVD）是缺血性和出血性中风的主要原因，也是血管性痴呆的主要原因。影响大脑的小穿透性血管。尽管目前遗传易感性研究取得了进展，在定义致病基因和潜在的病理生理机制方面仍然存在挑战。这里,我们报道ARHGEF15基因是与常染色体显性遗传CSVD相关的因果基因.我们确定了ARHGEF15基因的一个杂合非同义突变，该突变在两个CSVD家族中完全分离，以及两个散发性CSVD个体中的杂合非同义突变和停止增益突变，分别。有趣的是，临床影像学和病理结果显示,所有ARHGEF15突变携带者均出现严重的骨质疏松甚至骨质疏松性骨折.体外实验表明，ARHGEF15突变通过抑制成骨细胞的Wnt/β-catenin信号通路，导致RhoA/ROCK2失活诱导血管平滑肌细胞和内皮细胞的F-肌动蛋白骨架细胞分裂和成骨细胞功能障碍。此外，Arhgef15-e(V368M)1转基因小鼠出现CSVD样病理和行为表型,伴有严重的骨质疏松症。一起来看,我们的研究结果为ARHGEF15基因的功能缺失突变导致CSVD并伴有骨质疏松性骨折提供了有力证据.
