ArticleCardiovascular research2024
FLT4 causes developmental disorders of the cardiovascular and lymphovascular systems via pleiotropic molecular mechanisms.
Article in Cardiovascular research, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Article
- [Research progress on vascular endothelial growth factor C in meningeal lymphatic vessel-mediated clearance of amyloid β-protein].Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences · 2026Review
- Multidimensional single-cell analysis reveals immune dysfunction and inflammatory response in lymphatic malformations.Protein & cell · 2026Article
- Review
- RNA-sequencing unveils FLT4 splice site variants in variable congenital heart disease.European journal of human genetics : EJHG · 2025Article
- Phenotype and genetic variation analysis of primary congenital lymphedema caused by FLT4 gene mutations in a fetus.Frontiers in genetics · 2025Article
- Lymphatic System Development and Function.Current cardiology reports · 2024Review
- FLT4 gene polymorphisms influence isolated ventricular septal defect predisposition in a Southwest China population.BMC medical genomics · 2024Article
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Authors and funding
6 authors.
Funding
Abstract
aimsRare, deleterious genetic variants in FLT4 are associated with Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease. The distinct genetic variants in FLT4 are also an established cause of Milroy disease, the most prevalent form of primary hereditary lymphoedema. The phenotypic features of these two conditions are non-overlapping, implying pleiotropic cellular mechanisms during development. METHODS AND
resultsIn this study, we show that FLT4 variants identified in patients with TOF, when expressed in primary human endothelial cells, cause aggregation of FLT4 protein in the perinuclear endoplasmic reticulum, activating proteostatic and metabolic signalling, whereas lymphoedema-associated FLT4 variants and wild-type (WT) FLT4 do not. FLT4 TOF variants display characteristic gene expression profiles in key developmental signalling pathways, revealing a role for FLT4 in cardiogenesis distinct from its role in lymphatic development. Inhibition of proteostatic signalling abrogates these effects, identifying potential avenues for therapeutic intervention. Depletion of flt4 in zebrafish caused cardiac phenotypes of reduced heart size and altered heart looping. These phenotypes were rescued with coinjection of WT human FLT4 mRNA, but incompletely or not at all by mRNA harbouring FLT4 TOF variants.
conclusionTaken together, we identify a pathogenic mechanism for FLT4 variants predisposing to TOF that is distinct from the known dominant negative mechanism of Milroy-causative variants. FLT4 variants give rise to conditions of the two circulatory subdivisions of the vascular system via distinct developmental pleiotropic molecular mechanisms.
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