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

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.

• Authors: Noeline Nadarajah, Dörte Schulte, Vivienne McConnell, Silvia Martin-Almedina, Christina Karapouliou, Peter S Mortimer, Steve Jeffery, Stefan Schulte-Merker, Kristiana Gordon, Sahar Mansour, Pia Ostergaard
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 19 Issue 8 (Aug 01 2018) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 30071673 (Publication Type: Case Reports, Journal Article)

Chemical References

• VEGFC protein, human
• Vascular Endothelial Growth Factor C

Topics

• Animals
• Animals, Genetically Modified (genetics, metabolism)
• Arthrogryposis (genetics, metabolism, pathology)
• Child, Preschool
• Cleft Palate (genetics, metabolism, pathology)
• Clubfoot (genetics, metabolism, pathology)
• Female
• Frameshift Mutation
• Hand Deformities, Congenital (genetics, metabolism, pathology)
• Humans
• Infant
• Infant, Newborn
• Male
• Protein Domains
• RNA Splicing (genetics)
• Vascular Endothelial Growth Factor C (genetics, metabolism)
• Zebrafish (genetics, metabolism)