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 Gotô, Shin‐Ichiro Takahashi, Tetsuo Ushiku, Shumpei Ishikawa, Mutsumi Okazaki, Shinichi Morishita, Shoji Tsuji, Nobuhito Saito
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.