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

Nadarajah, Noeline; Schulte, Dörte; McConnell, Vivienne; Martin-Almedina, Silvia; Karapouliou, Christina; Mortimer, Peter S.; Jeffery, Steve; Schulte-Merker, Stefan; Gordon, Kristiana; Mansour, Sahar; Ostergaard, Pia

doi:10.3390/ijms19082259

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

Noeline Nadarajah

^1,†,

Dörte Schulte

^2,3,†,

Vivienne McConnell

⁴,

Silvia Martin-Almedina

Christina Karapouliou

¹,

Peter S. Mortimer

¹,

Steve Jeffery

¹,

Stefan Schulte-Merker

^2,3

Kristiana Gordon

¹,

Sahar Mansour

^1,5 and

Pia Ostergaard

^1,*

Molecular and Clinical Sciences Institute, St George’s University of London, London SW17 0RE, UK

Institute of Cardiovascular Organogenesis and Regeneration, Faculty of Medicine, WWU Münster, 48149 Münster, Germany

CiM Cluster of Excellence (EXC1003 CiM), University of Münster, 48149 Münster, Germany

⁴

Northern Ireland Regional Genetics Service, Belfast City Hospital, Belfast Health and Social Care Trust, Belfast BT9 7AB, UK

⁵

South West Thames Regional Genetics Unit, St George’s University Hospitals, London SW17 0RE, UK

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2018, 19(8), 2259; https://doi.org/10.3390/ijms19082259

Received: 5 July 2018 / Revised: 26 July 2018 / Accepted: 27 July 2018 / Published: 1 August 2018

(This article belongs to the Special Issue Vascular Endothelial Cells)

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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. View Full-Text

Keywords: primary lymphedema; Milroy; VEGFC; VEGFR3; FLT4

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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. A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon. Int. J. Mol. Sci. 2018, 19, 2259. https://doi.org/10.3390/ijms19082259

AMA Style

Nadarajah N, Schulte D, McConnell V, Martin-Almedina S, Karapouliou C, Mortimer PS, Jeffery S, Schulte-Merker S, Gordon K, Mansour S, Ostergaard P. A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon. International Journal of Molecular Sciences. 2018; 19(8):2259. https://doi.org/10.3390/ijms19082259

Chicago/Turabian Style

Nadarajah, Noeline, Dörte Schulte, Vivienne McConnell, Silvia Martin-Almedina, Christina Karapouliou, Peter S. Mortimer, Steve Jeffery, Stefan Schulte-Merker, Kristiana Gordon, Sahar Mansour, and Pia Ostergaard. 2018. "A Novel Splice-Site Mutation in VEGFC Is Associated with Congenital Primary Lymphoedema of Gordon" International Journal of Molecular Sciences 19, no. 8: 2259. https://doi.org/10.3390/ijms19082259

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

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