Pathogenic variants in HGF give rise to childhood-to-late onset primary lymphoedema by loss of function

错义突变 等位基因 肝细胞生长因子 医学 胡说 损失函数 无义突变 免疫学 淋巴系统 癌症研究 内科学 生物 表型 受体 遗传学 基因
作者
Murat Alpaslan,Elodie Fastré,Sandrine Mestre,Arie van Haeringen,Gabriela M. Repetto,Kathelijn Keymolen,Laurence M. Boon,Florence Belva,Guido Giacalone,Nicole Revençu,Yves Sznajer,Katie Riches,Vaughan Keeley,Sahar Mansour,Kristiana Gordon,Silvia Martin‐Almedina,Sara E. Dobbins,Pia Østergaard,I. Quéré,Pascal Brouillard
出处
期刊:Human Molecular Genetics [Oxford University Press]
卷期号:33 (14): 1250-1261
标识
DOI:10.1093/hmg/ddae060
摘要

Abstract Developmental and functional defects in the lymphatic system are responsible for primary lymphoedema (PL). PL is a chronic debilitating disease caused by increased accumulation of interstitial fluid, predisposing to inflammation, infections and fibrosis. There is no cure, only symptomatic treatment is available. Thirty-two genes or loci have been linked to PL, and another 22 are suggested, including Hepatocyte Growth Factor (HGF). We searched for HGF variants in 770 index patients from the Brussels PL cohort. We identified ten variants predicted to cause HGF loss-of-function (six nonsense, two frameshifts, and two splice-site changes; 1.3% of our cohort), and 14 missense variants predicted to be pathogenic in 17 families (2.21%). We studied co-segregation within families, mRNA stability for non-sense variants, and in vitro functional effects of the missense variants. Analyses of the mRNA of patient cells revealed degradation of the nonsense mutant allele. Reduced protein secretion was detected for nine of the 14 missense variants expressed in COS-7 cells. Stimulation of lymphatic endothelial cells with these 14 HGF variant proteins resulted in decreased activation of the downstream targets AKT and ERK1/2 for three of them. Clinically, HGF-associated PL was diverse, but predominantly bilateral in the lower limbs with onset varying from early childhood to adulthood. Finally, aggregation study in a second independent cohort underscored that rare likely pathogenic variants in HGF explain about 2% of PL. Therefore, HGF signalling seems crucial for lymphatic development and/or maintenance in human beings and HGF should be included in diagnostic genetic screens for PL.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
zz包子完成签到,获得积分20
刚刚
刚刚
刘松完成签到,获得积分20
刚刚
刚刚
1秒前
wishe发布了新的文献求助20
1秒前
淡然的铭发布了新的文献求助10
1秒前
LHTTT完成签到,获得积分10
1秒前
小邓完成签到,获得积分10
2秒前
酒笙完成签到,获得积分10
2秒前
2秒前
ding应助Promise采纳,获得10
2秒前
2秒前
2秒前
迷人耗子精完成签到,获得积分10
2秒前
丫丫完成签到 ,获得积分10
3秒前
wst1988完成签到,获得积分10
3秒前
3秒前
756333725完成签到,获得积分10
3秒前
3秒前
二手的科学家完成签到,获得积分10
3秒前
刘松发布了新的文献求助10
4秒前
LIXI完成签到,获得积分20
5秒前
chenxuan完成签到,获得积分10
5秒前
CHyaa完成签到,获得积分10
5秒前
牛大壮完成签到,获得积分10
5秒前
优美的梦菲完成签到,获得积分10
6秒前
沛沛完成签到,获得积分10
6秒前
6秒前
kk子发布了新的文献求助10
6秒前
756333725发布了新的文献求助10
7秒前
7秒前
LHTTT发布了新的文献求助10
7秒前
zy_完成签到,获得积分10
7秒前
与你共奋发布了新的文献求助10
7秒前
Jiaming应助xjb采纳,获得10
7秒前
小李发布了新的文献求助10
7秒前
ZM完成签到,获得积分10
7秒前
刘大可完成签到,获得积分10
8秒前
帕芙芙完成签到,获得积分10
8秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
Cognitive Neuroscience: The Biology of the Mind 1000
Technical Brochure TB 814: LPIT applications in HV gas insulated switchgear 1000
Immigrant Incorporation in East Asian Democracies 600
Nucleophilic substitution in azasydnone-modified dinitroanisoles 500
不知道标题是什么 500
A Preliminary Study on Correlation Between Independent Components of Facial Thermal Images and Subjective Assessment of Chronic Stress 500
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3968771
求助须知:如何正确求助?哪些是违规求助? 3513646
关于积分的说明 11169065
捐赠科研通 3249011
什么是DOI,文献DOI怎么找? 1794589
邀请新用户注册赠送积分活动 875236
科研通“疑难数据库(出版商)”最低求助积分说明 804740