Decreased Kinase Activity of the VEGFR3 Variant c.3175G>C Associated with Primary Lymphedema

TL;DR

This study shows that a specific VEGFR3 gene variant reduces kinase activity, contributing to primary lymphedema.

Contribution

The study experimentally confirms the pathogenicity of the VEGFR3 c.3175G>C variant in primary lymphedema.

Findings

The c.3175G>C FLT4 variant reduces VEGFR3 phosphorylation in response to VEGFC.

Cells with the c.3175G>C variant show decreased FLT4 expression compared to wild-type.

The variant is confirmed to play a pathogenic role in primary lymphedema.

Abstract

Vascular endothelial growth factor receptor 3 (VEGFR3) assumes a pivotal role in regulating the development and maintaining the structural integrity of the lymphatic system. Decreased activity of VEGFR3 can precipitate aplasia or hypoplasia of lymphatic system components, culminating in primary lymphedema. To date, numerous genetic variants have been identified within the FLT4 gene, which encodes VEGFR3; however, the majority of these remain uncharacterised and are classified as ‘variants of uncertain significance’. In preceding investigations involving FLT4 sequence analysis conducted on individuals presenting with primary lymphedema, we identified several rare genetic variants that possess the potential to modulate the functional activity of VEGFR3, including the heterozygous variant c.3175G>C (p.A1059P). Preliminary assessments encompassing clinical characteristics, family history, and predictive computational algorithms indicated that this variant was likely pathogenic. Consequently, this study presents the results of functional evaluation of the mutant VEGFR3 activity in cell models overexpressing the FLT4 variant c.3175G>C. VEGFC-dependent VEGFR3 phosphorylation and FLT4 expression were reduced in cells with c.3175G>C FLT4 variant compared to wild-type, confirming the pathogenic role of c.3175G>C in primary lymphedema.

Figures