Somatic GJA4 mutation in intracranial extra-axial cavernous hemangiomas  

作　　者：Ran Huo Yingxi Yang Hongyuan Xu Shaozhi Zhao Dong Song Jiancong Weng Ruochen Ma Yingfan Sun Jie Wang Yuming Jiao Junze Zhang Qiheng He Ruolei Wu Shuo Wang Ji-Zong Zhao Junting Zhang Jiguang Wang Yong Cao 

机构地区：[1]Department of Neurosurgery,Beijing Tiantan Hospital,Capital Medical University,Beijing,China [2]China National Clinical Research Center for Neurological Diseases,Beijing,China [3]Department of Chemical and Biological Engineering,The Hong Kong University of Science and Technology,Hong Kong,China [4]Division of Life Science,Center for Systems Biology and Human Health and State Key Laboratory of Molecular Neuroscience,The Hong Kong University of Science and Technology,Hong Kong,China [5]Department of Neurosurgery,China-Japan Friendship Hospital,Beijing,China [6]School of Medical Technology,Beijing Institute of Technology,Beijing,China [7]Hong Kong Center for Neurodegenerative Diseases,InnoHK,Hong Kong SAR,China [8]Beijing Neurosurgical Institute,Capital Medical University,Beijing,China

出　　处：《Stroke & Vascular Neurology》2023年第6期453-462,I0003-I0037,共45页卒中与血管神经病学（英文）

基　　金：Genomics Platform Construction for Chinese Major Brain Disease-AVM(PXM2019_026280_000002-AVM);Beijing Advanced Innovation Center for Big Data-based Precision Medicine(PXM2020_014226_000066);Hong Kong RGC Fund(16102522,C6021-19EF);Hong Kong ITC Fund(ITCPD/17-9)and Department of Science and Technology of Guangdong Province(2020A0505090007).

摘　　要：Objective Extra-axial cavernous hemangiomas(ECHs)are sporadic and rare intracranial occupational lesions that usually occur within the cavernous sinus.The aetiology of ECHs remains unknown.Methods Whole-exome sequencing was performed on ECH lesions from 12 patients(discovery cohort)and droplet digital polymerase-chain reaction(ddPCR)was used to confirm the identified mutation in 46 additional cases(validation cohort).Laser capture microdissection(LCM)was carried out to capture and characterise subgroups of tissue cells.Mechanistic and functional investigations were carried out in human umbilical vein endothelial cells and a newly established mouse model.Results We detected somatic GJA4 mutation(c.121G>T,p.G41C)in 5/12 patients with ECH in the discovery cohort and confirmed the finding in the validation cohort(16/46).LCM followed by ddPCR revealed that the mutation was enriched in lesional endothelium.In vitro experiments in endothelial cells demonstrated that the GJA4 mutation activated SGK-1 signalling that in turn upregulated key genes involved in cell hyperproliferation and the loss of arterial specification.Compared with wild-type littermates,mice overexpressing the GJA4 mutation developed ECH-like pathological morphological characteristics(dilated venous lumen and elevated vascular density)in the retinal superficial vascular plexus at the postnatal 3 weeks,which were reversed by an SGK1 inhibitor,EMD638683.Conclusions We identified a somatic GJA4 mutation that presents in over one-third of ECH lesions and proposed that ECHs are vascular malformations due to GJA4-induced activation of the SGK1 signalling pathway in brain endothelial cells.

关 键 词：INTRACRANIAL SUPERFICIAL HEMANGIOMA 

分 类 号：R739.41[医药卫生—肿瘤]