Functional characterization of variants found in Japanese patients with hereditary hemorrhagic telangiectasia

Author:

Morita Shuhei12ORCID,Nomura Shunsuke34,Azuma Kenko1,Chida‐Nagai Ayako5,Furutani Yoshiyuki6ORCID,Inai Kei6,Inoue Tatsuya7,Niimi Yasunari8,Iizuka Yuo9,Tsutsumi Yoshiyuki10,Ishizaki Reina11,Yamagishi Hiroyuki1112,Kawamata Takakazu2,Akagawa Hiroyuki1

Affiliation:

1. Institute for Comprehensive Medical Sciences Tokyo Women's Medical University Tokyo Japan

2. Department of Neurosurgery Tokyo Women's Medical University Tokyo Japan

3. Department of Neurosurgery Tokyo Women's Medical University Yachiyo Medical center Yachiyo Japan

4. Krembil Brain Institute University Health Network, University of Toronto Toronto Ontario Canada

5. Department of Pediatrics Hokkaido University Hospital Sapporo Japan

6. Department of Pediatric Cardiology and Adult Congenital Cardiology Tokyo Women's Medical University Tokyo Japan

7. Department of Neurosurgery St. Luke's International Hospital Tokyo Japan

8. Department of Neuroendovascular Therapy St. Luke's International Hospital Tokyo Japan

9. Department of Neuroradiology Kashiwa Tanaka Hospital Kashiwa Japan

10. Department of Radiology National Center for Child Health and Development Tokyo Japan

11. Department of Pediatrics Keio University School of Medicine Tokyo Japan

12. Center for Preventive Medicine Keio University School of Medicine Tokyo Japan

Abstract

AbstractHereditary 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.

Publisher

Wiley

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3