Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema

Primary lymphoedema is a rare, autosomal dominant disorder that leads to a disabling and disfiguring swelling of the extremities and, when untreated, tends to worsen with time. Here we link primary human lymphoedema to the FL T4 locus, encoding vascular endothelial growth factor receptor-3 (VEGFR-3). in several families. All disease-associated alleles analysed had missense mutations and encoded proteins with an inactive tyrosine kinase, preventing downstream gene activation, Our study establishes that VEGFR-3 is importan t for normal lymphatic vascular function and that mutations interfering wit h VEGFR-3 signal transduction are a cause of primary lymphoedema.