Preliminary Study On The Mechanism Of ARHGEF17 Mutation Leading To Intracranial Aneurysm

BackgroundIntracranial Aneurysm?IA?is usually a late-onset disease,affecting 1-3%of the general population and leading to life-threatening subarachnoid hemorrhage?SAH?.Genetic susceptibility has been implicated in IAs but the causative genes remain elusive.Methods and ResultsWe performed next-generation sequencing?NGS?in a discovery cohort of 20Chinese IA patients.Bioinformatics filters were exploited to search for candidate deleterious variants with rare and low allele frequency.We further examined the candidate variants in a multi-ethnic sample collection of 86 whole-exome sequenced unsolved familial IA cases from three previously published studies.We identified that the low-frequency variant c.4394C>A_p.Ala1465Asp?rs2298808?of ARHGEF17was significantly associated with IA in our Chinese discovery cohort(P=7×10^-4;OR=7.34).It was subsequently replicated in Japanese familial IA patients?P=0.04;OR=4.00;95%CI=0.832-14.8?and was associated with IA in the large Chinese sample collection comprising 1,031 sporadic IA-affected and 599 control individuals?P=0.023;OR=1.55;95%CI=1.00-2.46?.When combining the sequencing data of all familial IA patients from four different ethnicities?i.e.Chinese,Japanese,European American,and French-Canadian?,we identified a significantly increased mutation burden for ARHGEF17?21/106 versus 11/306;P=8.1×10-7;OR=6.6;95%CI=2.9-15.8?in cases as compared to controls.In zebrafish,ARHGEF17 was highly expressed in the brain blood vessel.ARHGEF17 knockdown caused blood extravasation in the brain region.Endothelial lesions were identified exclusively on cerebral blood vessels in the ARHGEF17-deficient zebrafish.The authors knocked down ARHGEF17 in HUVEC by lentiviral shRNA,and found 190 up-regulated and141 down-regulated differential genes by RNA-seq technology,and we performed GO enrichment analysis and KEEG enrichment analysis on these differential genes.Differential genes are enriched for inflammatory and intercellular junction pathways associated with IA.ConclusionsARHGEF17 is a risk gene for IA.The ARHGEF17 mutation may destroy the inflammatory levels and intercellular connections of intracranial blood vessels and damage the cerebral blood vessels to promote the development and progression of IA.Of course,this hypothesis needs to be further verified in the future by IA mouse models and molecular biology experiments.