title: Mutation in vascular endothelial growth factor-C, a ligand for vascular endothelial growth factor receptor-3, is associated with autosomal dominant milroy-like primary lymphedema.
abstract: BACKGROUND
  Mutations in vascular endothelial growth factor (VEGF) receptor-3 (VEGFR3 or FLT4) cause Milroy disease, an autosomal dominant condition that presents with congenital lymphedema. Mutations in VEGFR3 are identified in only 70% of patients with classic Milroy disease, suggesting genetic heterogeneity.
  
  
  OBJECTIVE
  To investigate the underlying cause in patients with clinical signs resembling Milroy disease in whom sequencing of the coding region of VEGFR3 did not reveal any pathogenic variation.
  
  
  RESULTS
  Exome sequencing of 5 such patients was performed, and a novel frameshift variant, c.571_572insTT in VEGFC, a ligand for VEGFR3, was identified in 1 proband. The variant cosegregated with the affected status in the family. An assay to assess the biological function of VEGFC activity in vivo, by expressing human VEGFC in the zebrafish floorplate was established. Forced expression of wild-type human VEGFC in the floorplate of zebrafish embryos leads to excessive sprouting in neighboring vessels. However, when overexpressing the human c.571_572insTT variant in the floorplate, no sprouting of vessels was observed, indicating that the base changes have a marked effect on the activity of VEGFC.
  
  
  CONCLUSIONS
  We propose that the mutation in VEGFC is causative for the Milroy disease-like phenotype seen in this family. This is the first time a mutation in one of the ligands of VEGFR3 has been reported to cause primary lymphedema.
authors: Human Genetics Research Centre, Biomedical Sciences, St George's University of London, London, United Kingdom.
authors: Kristiana
authors: K
authors: Gordon
authors: Dörte
authors: D
authors: Schulte
authors: Glen
authors: G
authors: Brice
authors: Michael A
authors: MA
authors: Simpson
authors: M Guy
authors: MG
authors: Roukens
authors: Andreas
authors: A
authors: van Impel
authors: Fiona
authors: F
authors: Connell
authors: Kamini
authors: K
authors: Kalidas
authors: Steve
authors: S
authors: Jeffery
authors: Peter S
authors: PS
authors: Mortimer
authors: Sahar
authors: S
authors: Mansour
authors: Stefan
authors: S
authors: Schulte-Merker
authors: Pia
authors: P
authors: Ostergaard
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002648:Child; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D006801:Humans; D008209:Lymphedema / Q000151:congenital / Q000235:genetics* / Q000473:pathology; D008297:Male; D010375:Pedigree; D010641:Phenotype; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics*; D055815:Young Adult; D015027:Zebrafish
chemical_list: C467486:VEGFC protein, human; D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3