FLT4 causes developmental disorders of the cardiovascular and lymphovascular systems via pleiotropic molecular mechanisms.

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 varia

SUBMITTER: Monaghan RM 

PROVIDER: S-EPMC11368125 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature