Somatic GJA4 gain-of-function mutation in orbital cavernous venous malformations
Hiroki Hongo1, Satoru Miyawaki2, Yu Teranishi1
1Department of Neurosurgery, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
Angiogenesis
|July 28, 2022
Summary
A novel GJA4 gene mutation (p.Gly41Cys) was identified in orbital cavernous venous malformations (OCVM). This gain-of-function mutation leads to hyperactive hemichannels, suggesting a new mechanism in vascular anomaly development.
Area of Science:
- Vascular Biology
- Genetics
- Ophthalmology
Background:
- Orbital cavernous venous malformations (OCVM) are vascular anomalies with unknown causes.
- OCVMs are characterized by abnormal dilation of vascular channels.
Purpose of the Study:
- To investigate the genetic basis of OCVM.
- To identify potential driver mutations in OCVM development.
Main Methods:
- Somatic mutation analysis in OCVM tissues.
- Immunohistochemistry to detect GJA4 expression.
- Xenopus oocyte electrophysiology to assess channel function.
- Cellular integrity assays in endothelial cells.
Main Results:
- A recurrent somatic missense mutation (c.121G>T, p.Gly41Cys) in the GJA4 gene was found in 96.2% of OCVM tissues.
- GJA4 expression was confirmed in OCVM endothelial cells and stroma.
- The GJA4 mutation resulted in a hyperactive hemichannel gain-of-function.
- Overexpression of mutant GJA4 caused loss of endothelial cell integrity, reversible with a hemichannel inhibitor.
Conclusions:
- The GJA4 p.Gly41Cys mutation is a likely driver mutation in OCVM.
- Hyperactive hemichannels contribute to the pathogenesis of this vascular anomaly.
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