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
-
- Hand Deformities, Congenital/genetics*
- Hand Deformities, Congenital/metabolism
- Hand Deformities, Congenital/pathology
- Protein Domains
- RNA Splicing/genetics*
- Humans
- Child, Preschool
- Male
- Cleft Palate/genetics*
- Cleft Palate/metabolism
- Cleft Palate/pathology
- Frameshift Mutation*
- Animals
- Arthrogryposis/genetics*
- Arthrogryposis/metabolism
- Arthrogryposis/pathology
- Female
- Infant, Newborn
- Zebrafish/genetics
- Zebrafish/metabolism
- Vascular Endothelial Growth Factor C/genetics*
- Vascular Endothelial Growth Factor C/metabolism
- Animals, Genetically Modified/genetics
- Animals, Genetically Modified/metabolism
- Infant
- Clubfoot/genetics*
- Clubfoot/metabolism
- Clubfoot/pathology
- PubMed
- 30071673 Full text @ Int. J. Mol. Sci.
Citation
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. (2018) A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon.. International Journal of Molecular Sciences. 19(8).
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
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping