PUBLICATION
FLT4 causes developmental disorders of the cardiovascular and lymphovascular systems via pleiotropic molecular mechanisms
- Authors
- Monaghan, R.M., Naylor, R.W., Flatman, D., Kasher, P.R., Williams, S.G., Keavney, B.D.
- ID
- ZDB-PUB-240508-4
- Date
- 2024
- Source
- Cardiovascular research 120(10): 1164-1176 (Journal)
- Registered Authors
- Kasher, Paul, Naylor, Richard
- Keywords
- FLT4, Tetralogy of Fallot, VEGFR3, congenital heart disease, developmental pleiotropy, primary lymphoedema, proteostasis
- MeSH Terms
-
- Animals
- Tetralogy of Fallot*/genetics
- Tetralogy of Fallot*/metabolism
- Tetralogy of Fallot*/pathology
- Signal Transduction*
- Endoplasmic Reticulum/genetics
- Endoplasmic Reticulum/metabolism
- Endoplasmic Reticulum/pathology
- Gene Expression Regulation, Developmental
- Cells, Cultured
- Human Umbilical Vein Endothelial Cells/metabolism
- Human Umbilical Vein Endothelial Cells/pathology
- Lymphedema/genetics
- Lymphedema/metabolism
- Lymphedema/pathology
- Lymphedema/physiopathology
- Vascular Endothelial Growth Factor Receptor-3*/genetics
- Vascular Endothelial Growth Factor Receptor-3*/metabolism
- Humans
- Zebrafish*/genetics
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Mutation
- Phenotype
- Genetic Predisposition to Disease
- Endothelial Cells/metabolism
- Endothelial Cells/pathology
- PubMed
- 38713105 Full text @ Cardiovasc. Res.
Citation
Monaghan, R.M., Naylor, R.W., Flatman, D., Kasher, P.R., Williams, S.G., Keavney, B.D. (2024) FLT4 causes developmental disorders of the cardiovascular and lymphovascular systems via pleiotropic molecular mechanisms. Cardiovascular research. 120(10):1164-1176.
Abstract
Aims Rare, deleterious genetic variants in FLT4 are associated with Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease (CHD). Distinct genetic variants in FLT4 are also an established cause of Milroy disease, the most prevalent form of primary hereditary lymphoedema. Phenotypic features of these two conditions are non-overlapping, implying pleiotropic cellular mechanisms during development.
Methods and results Here, we show that FLT4 variants identified in TOF patients, 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 wildtype 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 wildtype human FLT4 mRNA, but incompletely or not at all by mRNA harbouring FLT4 TOF variants.
Conclusions Taken 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.
Translational perspective Proteostatic dysfunction, if confirmed as a mechanism of CHD pathogenesis for other predisposing genes, may identify pathways to therapeutic interventions. Distinguishing mechanistically how variants in FLT4 give rise to CHD may have potential to individualise genetic counselling in affected families.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping