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

Gordon, K., Schulte, D., Brice, G., Simpson, M.A., Roukens, M.G., van Impel, A.W., Connell, F., Kalidas, K., Jeffery, S., Mortimer, P.S., Mansour, S., Schulte-Merker, S., and Ostergaard, P.
Circulation research   112(6): 956-60 (Journal)
Registered Authors
Connell, Fiona, Schulte-Merker, Stefan, van Impel, Andreas
primary lymphedema, Milroy Disease, VEGFC, VEGFR3, FLT4, lymphatic capillary, vascular endothelial growth factor, vascular endothelial growth factor receptor
MeSH Terms
  • Adolescent
  • Adult
  • Animals
  • Child
  • Female
  • Frameshift Mutation/genetics*
  • Humans
  • Lymphedema/congenital
  • Lymphedema/genetics*
  • Lymphedema/pathology
  • Male
  • Pedigree
  • Phenotype
  • Vascular Endothelial Growth Factor C/genetics*
  • Vascular Endothelial Growth Factor Receptor-3/genetics*
  • Young Adult
  • Zebrafish
23410910 Full text @ Circ. Res.

Rationale: Mutations in VEGFR3 (FLT4) cause Milroy Disease (MD), an autosomal dominant condition that presents with congenital lymphedema. Mutations in VEGFR3 are identified in only 70% of patients with classic MD, suggesting genetic heterogeneity.

Objective: To investigate the underlying cause in patients with clinical signs resembling MD in whom sequencing of the coding region of VEGFR3 did not reveal any pathogenic variation.

Methods and Results: Exome sequencing of five such patients was performed and a novel frameshift variant, c.571_572insTT in VEGFC, a ligand for VEGFR3, was identified in one proband. The variant co-segregated 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 wildtype human VEGFC in the floorplate of zebrafish embryos leads to excessive sprouting in neighbouring 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 MD-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.

Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes