2025-06-11 東京科学大学
図 血管狭窄の表現型と責任遺伝子、その病態の関連を示した模式図
<関連情報>
- https://www.isct.ac.jp/ja/news/l9qkjrrvfazr
- https://www.isct.ac.jp/plugins/cms/component_download_file.php?type=2&pageId=&contentsId=1&contentsDataId=1545&prevId=&key=5ccd5d5a5506de93327b3366b731c540.pdf
- https://insight.jci.org/articles/view/190094
RINGフィンガータンパク質213のデノボ変異が全身性血管症を引き起こす De novo variant in RING finger protein 213 causes systemic vasculopathy
Ayako Kashimada, Tomoko Mizuno, Eriko Tanaka, Susumu Hosokawa, Tomohiro Udagawa, Yuichi Hiraoka, Keisuke Uchida, Tomohiro Morio, Kenjiro Kosaki, and Masatoshi Takagi
JCI Insight Published: June 9, 2025
DOI:https://doi.org/10.1172/jci.insight.190094
Abstract
Systemic arterial stenosis, including moyamoya disease (MMD) and middle aortic syndrome (MAS), is a rare condition of unclear etiology. MMD is a cerebral angiopathy, and MAS affects the abdominal and thoracic aorta. Although some genetic associations with MAS have been identified, the causes remain elusive. In this study, de novo heterozygous missense variants of RING finger protein 213 (RNF213) (p.His4058Pro and p.Thr4155Pro) in 2 unrelated families with MAS and MMD were studied by whole-exome sequencing. To elucidate the significance of these variants, we produced knockin mice carrying the Rnf213 p.His4058Pro variant. Homozygous knockin mice exhibited perinatal lethality because of respiratory failure and lung dysplasia, suggesting that this variant is pathogenic. Lung dysplasia in homozygous knockin mice was associated with upregulated innate immunity and inflammatory responses and downregulated cell proliferation. These findings suggested that in mice, the RNF213 p.His4058Pro variant plays critical roles in regulation of innate immunity and inflammation that affect lung development, revealing the complexity of RNF213 function in various tissues and species. In conclusion, this study provides insights into the genetic basis of MAS and MMD, highlights the potential involvement of RNF213 variants in systemic vasculopathy, and identifies unexpected associations with lung development and immune processes.
