title: Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema.
abstract: 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 FLT4 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 important for normal lymphatic vascular function and that mutations interfering with VEGFR-3 signal transduction are a cause of primary lymphoedema.
authors.affiliation: Molecular/Cancer Biology Laboratory, Ludwig Institute for Cancer Research, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: M J
authors.initials: MJ
authors.lastname: Karkkainen
authors.forename: R E
authors.initials: RE
authors.lastname: Ferrell
authors.forename: E C
authors.initials: EC
authors.lastname: Lawrence
authors.forename: M A
authors.initials: MA
authors.lastname: Kimak
authors.forename: K L
authors.initials: KL
authors.lastname: Levinson
authors.forename: M A
authors.initials: MA
authors.lastname: McTigue
authors.forename: K
authors.initials: K
authors.lastname: Alitalo
authors.forename: D N
authors.initials: DN
authors.lastname: Finegold
mesh_terms: D000483:Alleles; D000818:Animals; D002460:Cell Line; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004795:Enzyme Stability; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D006207:Half-Life; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008209:Lymphedema / Q000151:congenital* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D010766:Phosphorylation / Q000187:drug effects; D017433:Protein Structure, Secondary; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3
chemical_list: D016228:Endothelial Growth Factors; D011956:Receptors, Cell Surface; D011993:Recombinant Fusion Proteins; D042582:Vascular Endothelial Growth Factor C; D020794:Receptor Protein-Tyrosine Kinases; D040321:Vascular Endothelial Growth Factor Receptor-3