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

被引:12
|
作者
Nadarajah, Noeline [1 ]
Schulte, Doerte [2 ,3 ]
McConnell, Vivienne [4 ]
Martin-Almedina, Silvia [1 ]
Karapouliou, Christina [1 ]
Mortimer, Peter S. [1 ]
Jeffery, Steve [1 ]
Schulte-Merker, Stefan [2 ,3 ]
Gordon, Kristiana [1 ]
Mansour, Sahar [1 ,5 ]
Ostergaard, Pia [1 ]
机构
[1] St Georges Univ London, Mol & Clin Sci Inst, London SW17 0RE, England
[2] WWU Munster, Fac Med, Inst Cardiovasc Organogenesis & Regenerat, D-48149 Munster, Germany
[3] Univ Munster, CiM Cluster Excellence CiM EXC1003, D-48149 Munster, Germany
[4] Belfast Hlth & Social Care Trust, Northern Ireland Reg Genet Serv, Belfast City Hosp, Belfast BT9 7AB, Antrim, North Ireland
[5] St Georges Univ Hosp, South West Thames Reg Genet Unit, London SW17 0RE, England
关键词
primary lymphedema; Milroy; VEGFC; VEGFR3; FLT4; GROWTH-FACTOR-C; EMBRYONIC LYMPHANGIOGENESIS; MILROY DISEASE; MOUSE EMBRYOS; ZEBRAFISH; CCBE1; ACTIVATION; ANGIOGENESIS; RECEPTOR-3; ARTERIES;
D O I
10.3390/ijms19082259
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
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页数:15
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