2022年7月29日
Somatic GJA4 gain-of-function mutation in orbital cavernous venous malformations
Angiogenesis
- 巻
- 26
- 号
- 1
- 開始ページ
- 37
- 終了ページ
- 52
- 記述言語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1007/s10456-022-09846-5
- 出版者・発行元
- Springer Science and Business Media LLC
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.
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.
- リンク情報
-
- DOI
- https://doi.org/10.1007/s10456-022-09846-5
- PubMed
- https://www.ncbi.nlm.nih.gov/pubmed/35902510
- PubMed Central
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9908695
- URL
- https://link.springer.com/content/pdf/10.1007/s10456-022-09846-5.pdf
- URL
- https://link.springer.com/article/10.1007/s10456-022-09846-5/fulltext.html
- ID情報
-
- DOI : 10.1007/s10456-022-09846-5
- ISSN : 0969-6970
- eISSN : 1573-7209
- PubMed ID : 35902510
- PubMed Central 記事ID : PMC9908695