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
  • Phenotype
  • Vascular Endothelial Growth Factor Receptor-3*/genetics
  • Vascular Endothelial Growth Factor Receptor-3*/metabolism
  • Human Umbilical Vein Endothelial Cells/metabolism
  • Human Umbilical Vein Endothelial Cells/pathology
  • Cells, Cultured
  • Endoplasmic Reticulum/genetics
  • Endoplasmic Reticulum/metabolism
  • Endoplasmic Reticulum/pathology
  • Animals
  • Zebrafish Proteins*/genetics
  • Zebrafish Proteins*/metabolism
  • Tetralogy of Fallot*/genetics
  • Tetralogy of Fallot*/metabolism
  • Tetralogy of Fallot*/pathology
  • Mutation
  • Genetic Predisposition to Disease
  • Lymphedema/genetics
  • Lymphedema/metabolism
  • Lymphedema/pathology
  • Lymphedema/physiopathology
  • Endothelial Cells/metabolism
  • Endothelial Cells/pathology
  • Signal Transduction*
  • Humans
  • Zebrafish*/genetics
  • Gene Expression Regulation, Developmental
(all 27)
PubMed
38713105 Full text @ Cardiovasc. Res.
Abstract
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.
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.
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.
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
Figures
Figure Gallery (6 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
s843TgTransgenic Insertion
    1 - 1 of 1
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    Human Disease / Model
    Human Disease Fish Conditions Evidence
    tetralogy of FallotTAS
    1 - 1 of 1
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    Sequence Targeting Reagents
    Target Reagent Reagent Type
    flt4MO3-flt4MRPHLNO
    1 - 1 of 1
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    Fish
    1 - 4 of 4
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    Antibodies
    No data available
    Orthology
    No data available
    Engineered Foreign Genes
    Marker Marker Type Name
    EGFPEFGEGFP
    1 - 1 of 1
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    Mapping
    No data available