アカガワ　ヒロユキ   Akagawa Hiroyuki   赤川　浩之    所属   研究施設 研究施設    職種   准教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Functional characterization of variants found in Japanese patients with hereditary hemorrhagic telangiectasia.
掲載誌名	正式名：Clinical genetics 略　 称：Clin Genet ISSNコード：13990004/00099163
掲載区分	国外
巻・号・頁	Online ahead of print,pp.1-6
著者・共著者	Morita Shuhei, Nomura Shunsuke, Azuma Kenko, Chida-Nagai Ayako, Furutani Yoshiyuki, Inai Kei, Inoue Tatsuya, Niimi Yasunari, Iizuka Yuo, Tsutsumi Yoshiyuki, Ishizaki Reina, Yamagishi Hiroyuki, Kawamata Takakazu, Akagawa Hiroyuki
発行年月	2024/01
概要	Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant form of vascular dysplasia. Genetic diagnosis is made by identifying loss-of-function variants in genes, such as ENG and ACVRL1. However, the causal mechanisms of various variants of unknown significance remains unclear. In this study, we analyzed 12 Japanese patients from 11 families who were clinically diagnosed with HHT. Sequencing analysis identified 11 distinct variants in ACVRL1 and ENG. Three of the 11 were truncating variants, leading to a definitive diagnosis, whereas the remaining eight were splice-site and missense variants that required functional analyses. In silico splicing analyses demonstrated that three variants, c.526-3C > G and c.598C > G in ACVRL1, and c.690-1G > A in ENG, caused aberrant splicing, as confirmed by a minigene assay. The five remaining missense variants were p.Arg67Gln, p.Ile256Asn, p.Leu285Pro, and p.Pro424Leu in ACVRL and p.Pro165His in ENG. Nanoluciferase-based bioluminescence analyses demonstrated that these ACVRL1 variants impaired cell membrane trafficking, resulting in the loss of bone morphogenetic protein 9 (BMP9) signal transduction. In contrast, the ENG mutation impaired BMP9 signaling despite normal cell membrane expression. The updated functional analysis methods performed in this study will facilitate effective genetic testing and appropriate medical care for patients with HHT.
DOI	10.1111/cge.14483
PMID	38225712