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

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 <i>FLT4</i> gene, which encodes VEGFR3; however, the majority of these remain uncharacterised and are classified as 'variants of uncertain significance'. In preceding investigations involving <i>FLT4</i> 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 <i>FLT4</i> variant c.3175G>C. VEGFC-dependent VEGFR3 phosphorylation and <i>FLT4</i> expression were reduced in cells with c.3175G>C <i>FLT4</i> variant compared to wild-type, confirming the pathogenic role of c.3175G>C in primary lymphedema.