Somatic GJA4 gain-of-function mutation in orbital cavernous venous malformations.
Somatic GJA4 gain-of-function mutation in orbital cavernous venous malformations.
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DOI：
10.1007/s10456-022-09846-5
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发表时间：
2023-03
期刊：
影响因子：
9.8
通讯作者：
中科院分区：
文献类型：
--
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眶海绵状静脉畸形（OCVM）是一种病因不明的散发性血管异常，其特征是血管通道异常扩张。在这里，我们在25/26 (96.2%)OCVM患者的OCVM组织中发现了一个体细胞错义突变，GJA4中的c.121G > T (p.Gly41Cys)，该突变编码一种跨膜蛋白，该蛋白是血管系统间隙连接和半通道的组成部分。免疫组化检测GJA4在OCVM组织包括内皮细胞和间质中的表达。在OCVM组织中，使用磁激活细胞分选获得的内皮细胞富集部分的突变等位基因频率更高。非洲爪蟾卵母细胞的全细胞电压箝位分析显示，GJA4 c.121G > T （p.Gly41Cys）是一个功能获得突变，导致形成一个过度活跃的半通道。突变蛋白在人脐静脉内皮细胞中的过度表达会导致细胞完整性的丧失，这可以通过卡贝诺洛酮（一种非特异性间隙连接/半通道抑制剂）来挽救。我们的数据表明GJA4 c.121G > T （p.Gly41Cys）是OCVM的潜在驱动基因突变。我们认为，过度活跃的半通道在这种血管表型的发展中起作用。在线版本包含补充材料，可在10.1007/s10456-022-09846-5获得。
Orbital cavernous venous malformation (OCVM) is a sporadic vascular anomaly of uncertain etiology characterized by abnormally dilated vascular channels. Here, we identify a somatic missense mutation, c.121G > T (p.Gly41Cys) in GJA4, which encodes a transmembrane protein that is a component of gap junctions and hemichannels in the vascular system, in OCVM tissues from 25/26 (96.2%) individuals with OCVM. GJA4 expression was detected in OCVM tissue including endothelial cells and the stroma, through immunohistochemistry. Within OCVM tissue, the mutation allele frequency was higher in endothelial cell-enriched fractions obtained using magnetic-activated cell sorting. Whole-cell voltage clamp analysis in Xenopus oocytes revealed that GJA4 c.121G > T (p.Gly41Cys) is a gain-of-function mutation that leads to the formation of a hyperactive hemichannel. Overexpression of the mutant protein in human umbilical vein endothelial cells led to a loss of cellular integrity, which was rescued by carbenoxolone, a non-specific gap junction/hemichannel inhibitor. Our data suggest that GJA4 c.121G > T (p.Gly41Cys) is a potential driver gene mutation for OCVM. We propose that hyperactive hemichannel plays a role in the development of this vascular phenotype. The online version contains supplementary material available at 10.1007/s10456-022-09846-5.
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