PUBLICATION

A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.

Authors
Nadarajah, N., Schulte, D., McConnell, V., Martin-Almedina, S., Karapouliou, C., Mortimer, P.S., Jeffery, S., Schulte-Merker, S., Gordon, K., Mansour, S., Ostergaard, P.
ID
ZDB-PUB-180804-1
Date
2018
Source
International Journal of Molecular Sciences   19(8): (Journal)
Registered Authors
Schulte-Merker, Stefan
Keywords
FLT4, Milroy, VEGFC, VEGFR3, primary lymphedema
MeSH Terms
  • Animals
  • Animals, Genetically Modified/genetics
  • Animals, Genetically Modified/metabolism
  • Arthrogryposis/genetics*
  • Arthrogryposis/metabolism
  • Arthrogryposis/pathology
  • Child, Preschool
  • Cleft Palate/genetics*
  • Cleft Palate/metabolism
  • Cleft Palate/pathology
  • Clubfoot/genetics*
  • Clubfoot/metabolism
  • Clubfoot/pathology
  • Female
  • Frameshift Mutation*
  • Hand Deformities, Congenital/genetics*
  • Hand Deformities, Congenital/metabolism
  • Hand Deformities, Congenital/pathology
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Protein Domains
  • RNA Splicing/genetics*
  • Vascular Endothelial Growth Factor C/genetics*
  • Vascular Endothelial Growth Factor C/metabolism
  • Zebrafish/genetics
  • Zebrafish/metabolism
PubMed
30071673 Full text @ Int. J. Mol. Sci.
Abstract
Lymphedema is characterized by chronic swelling of any body part caused by malfunctioning or obstruction in the lymphatic system. Primary lymphedema is often considered genetic in origin. VEGFC, which is a gene encoding the ligand for the vascular endothelial growth factor receptor 3 (VEGFR3/FLT4) and important for lymph vessel development during lymphangiogenesis, has been associated with a specific subtype of primary lymphedema. Through Sanger sequencing of a proband with bilateral congenital pedal edema resembling Milroy disease, we identified a novel mutation (NM_005429.2; c.361+5G>A) in VEGFC. The mutation induced skipping of exon 2 of VEGFC resulting in a frameshift and the introduction of a premature stop codon (p.Ala50ValfsTer18). The mutation leads to a loss of the entire VEGF-homology domain and the C-terminus. Expression of this Vegfc variant in the zebrafish floorplate showed that the splice-site variant significantly reduces the biological activity of the protein. Our findings confirm that the splice-site variant, c.361+5G>A, causes the primary lymphedema phenotype in the proband. We examine the mutations and clinical phenotypes of the previously reported cases to review the current knowledge in this area.
Genes / Markers
Figures
Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes