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.
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