Journal Article
Somatic GJA4 gain-of-function mutation in orbital cavernous venous malformations
Hiroki Hongo; Satoru Miyawaki; Yu Teranishi; Jun Mitsui; Hiroto Katoh; Daisuke Komura; Kinya Tsubota; Takashi Matsukawa; Masakatsu Watanabe; Masakazu Kurita; Jun Yoshimura; Shogo Dofuku; Kenta Ohara; Daiichiro Ishigami; Atsushi Okano; Motoi Kato; Fumihiko Hakuno; Ayaka Takahashi; Akiko Kunita; Hiroyuki Ishiura; Masahiro Shin; Hirofumi Nakatomi; Toshitaka Nagao; Hiroshi Goto; Shin-Ichiro Takahashi; Tetsuo Ushiku; Shumpei Ishikawa; Mutsumi Okazaki; Shinichi Morishita; Shoji Tsuji; Nobuhito Saito
Angiogenesis · Vol. 26, Issue 1 · pp. 37-52 · 2023
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.