FLT4 Causes Developmental Disorders of the Cardiovascular and Lymphovascular Systems Via Pleiotropic Molecular Mechanisms

Overview

Journal Cardiovasc Res

Specialty Cardiology & Vascular Diseases

Date 2024 May 7

PMID 38713105

Authors

Richard M Monaghan

Richard W Naylor

Daisy Flatman

Paul R Kasher

Simon G Williams

Bernard D Keavney

Affiliations

Soon will be listed here.

Abstract

Aims: Rare, 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 Results: In 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.

Conclusion: 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.

Citing Articles

Lymphatic System Development and Function.

Janardhan H, Wachter B, Trivedi C Curr Cardiol Rep. 2024; 26(11):1209-1219.

PMID: 39172295 DOI: 10.1007/s11886-024-02120-8.

FLT4 gene polymorphisms influence isolated ventricular septal defect predisposition in a Southwest China population.

Zhang Y, Dong X, Zhang J, Zhao M, Wang J, Chu J BMC Med Genomics. 2024; 17(1):197.

PMID: 39107825 PMC: 11302092. DOI: 10.1186/s12920-024-01971-y.

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