Details

Autor(en) / Beteiligte

• Hongo, Hiroki
• Miyawaki, Satoru
• Teranishi, Yu
• Mitsui, Jun
• Katoh, Hiroto
• Komura, Daisuke
• Tsubota, Kinya
• Matsukawa, Takashi
• Watanabe, Masakatsu
• Kurita, Masakazu
• Yoshimura, Jun
• Dofuku, Shogo
• Ohara, Kenta
• Ishigami, Daiichiro
• Okano, Atsushi
• Kato, Motoi
• Hakuno, Fumihiko
• Takahashi, Ayaka
• Kunita, Akiko
• Ishiura, Hiroyuki
• Shin, Masahiro
• Nakatomi, Hirofumi
• Nagao, Toshitaka
• Goto, Hiroshi
• Takahashi, Shin-Ichiro
• Ushiku, Tetsuo
• Ishikawa, Shumpei
• Okazaki, Mutsumi
• Morishita, Shinichi
• Tsuji, Shoji
• Saito, Nobuhito

Titel

Somatic GJA4 gain-of-function mutation in orbital cavernous venous malformations

Ist Teil von

• Angiogenesis (London), 2023-02, Vol.26 (1), p.37-52

Ort / Verlag

Dordrecht: Springer Netherlands

Erscheinungsjahr

2023

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.