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Angiogenesis
2023 Feb 01;261:37-52. doi: 10.1007/s10456-022-09846-5.
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Somatic GJA4 gain-of-function mutation in orbital cavernous venous malformations.
Hongo H
,
Miyawaki S
,
Teranishi Y
,
Mitsui J
,
Katoh H
,
Komura D
,
Tsubota K
,
Matsukawa T
,
Watanabe M
,
Kurita M
,
Yoshimura J
,
Dofuku S
,
Ohara K
,
Ishigami D
,
Okano A
,
Kato M
,
Hakuno F
,
Takahashi A
,
Kunita A
,
Ishiura H
,
Shin M
,
Nakatomi H
,
Nagao T
,
Goto H
,
Takahashi SI
,
Ushiku T
,
Ishikawa S
,
Okazaki M
,
Morishita S
,
Tsuji S
,
Saito N
.
???displayArticle.abstract???
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.
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