Missense Mutations Interfere With VEGFR-3 Signalling in Primary Lymphoedema

Nat Genet. 2000 Jun;25(2):153-9. doi: 10.1038/75997.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Animals
  • Cell Line
  • Chromosomes, Human, Pair 5 / genetics
  • Endothelial Growth Factors / pharmacology
  • Enzyme Stability
  • Female
  • Genes, Dominant / genetics
  • Half-Life
  • Humans
  • Infant
  • Infant, Newborn
  • Lymphedema / congenital*
  • Lymphedema / genetics*
  • Lymphedema / metabolism
  • Male
  • Mice
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation, Missense / genetics*
  • Pedigree
  • Phosphorylation / drug effects
  • Protein Structure, Secondary
  • Receptor Protein-Tyrosine Kinases / chemistry
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptors, Cell Surface / chemistry
  • Receptors, Cell Surface / genetics*
  • Receptors, Cell Surface / metabolism*
  • Recombinant Fusion Proteins / chemistry
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Signal Transduction* / drug effects
  • Transcriptional Activation / drug effects
  • Transcriptional Activation / genetics
  • Vascular Endothelial Growth Factor C
  • Vascular Endothelial Growth Factor Receptor-3

Substances

  • Endothelial Growth Factors
  • Receptors, Cell Surface
  • Recombinant Fusion Proteins
  • Vascular Endothelial Growth Factor C
  • Receptor Protein-Tyrosine Kinases
  • Vascular Endothelial Growth Factor Receptor-3

Associated data

  • GENBANK/S66407
  • GENBANK/X68203