期刊
CIRCULATION RESEARCH
卷 112, 期 6, 页码 956-U235出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.113.300350
关键词
FLT4; lymphatic capillary; Milroy disease; primary lymphedema; vascular endothelial growth factor; vascular endothelial growth factor receptor
资金
- Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre (BRC)
- St Thomas' National Health Service (NHS) Foundation
- King's College London
- King's College Hospital NHS Foundation Trust
- Biomics Centre, St. George's University of London
- British Heart Foundation [FS/11/40/28739, PG/10/58/28477]
- KNAW
- MC IEF
- Netherlands Organization for Scientific Research (NWO)
- British Heart Foundation [PG/10/58/28477, FS/11/40/28739] Funding Source: researchfish
Rationale: Mutations in vascular endothelial growth factor (VEGF) receptor-3 (VEGFR3 or FLT4) cause Milroy disease, an autosomal dominant condition that presents with congenital lymphedema. Mutations in VEGFR3 are identified in only 70% of patients with classic Milroy disease, suggesting genetic heterogeneity. Objective: To investigate the underlying cause in patients with clinical signs resembling Milroy disease in whom sequencing of the coding region of VEGFR3 did not reveal any pathogenic variation. Methods and Results: Exome sequencing of 5 such patients was performed, and a novel frameshift variant, c.571_572insTT in VEGFC, a ligand for VEGFR3, was identified in 1 proband. The variant cosegregated with the affected status in the family. An assay to assess the biological function of VEGFC activity in vivo, by expressing human VEGFC in the zebrafish floorplate was established. Forced expression of wild-type human VEGFC in the floorplate of zebrafish embryos leads to excessive sprouting in neighboring vessels. However, when overexpressing the human c.571_572insTT variant in the floorplate, no sprouting of vessels was observed, indicating that the base changes have a marked effect on the activity of VEGFC. Conclusions: We propose that the mutation in VEGFC is causative for the Milroy disease-like phenotype seen in this family. This is the first time a mutation in one of the ligands of VEGFR3 has been reported to cause primary lymphedema. (Circ Res. 2013;112:956-960.)
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