Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema

Abstract

Primary lymphoedema is a rare, autosomal dominant disorder that leads to a disabling and disfiguring swelling of the extremities and, when untreated, tends to worsen with time. Here we link primary human lymphoedema to the FLT4 locus, encoding vascular endothelial growth factor receptor-3 (VEGFR-3), in several families. All disease-associated alleles analysed had missense mutations and encoded proteins with an inactive tyrosine kinase, preventing downstream gene activation. Our study establishes that VEGFR-3 is important for normal lymphatic vascular function and that mutations interfering with VEGFR-3 signal transduction are a cause of primary lymphoedema.

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Figure 1: Pedigrees of four lymphoedema families linked to chromosome 5q.
Figure 2: Missense mutations in FLT4 alleles of the lymphoedema patients abolish the receptor tyrosyl phosphorylation.
Figure 3: Analysis of VEGFR-3 autophosphorylation in a ligand-dependent system.
Figure 4: The turnover times of mutant and wild-type VEGFR-3 analysed by pulse-chase labelling analysis.
Figure 5: Ability of wild-type and mutant VEGFR-3 to activate downstream gene expression.
Figure 6: Model of the VEGFR-3 protein fold showing the positions of lymphoedema-associated mutations.

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Acknowledgements

We thank J. Esman for clinical evaluation of the families; the family members for participation; and S. Karttunen, T. Tainola, A. Parsons, P. Ylikantola and M. Helantera for technical assistance. This study was supported by grants from the Finnish Cancer Organization, Finnish Cultural Foundation, Emil Aaltonen Foundation, Ida Montini Foundation, the Finnish Academy and the European Union (Biomed grant no. PL 963380), N.I.H. grant no. HD35174 and a grant from the D.T. Watson Rehabilitation Hospital.

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Correspondence to Robert E. Ferrell.

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Karkkainen, M., Ferrell, R., Lawrence, E. et al. Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema . Nat Genet 25, 153–159 (2000). https://doi.org/10.1038/75997

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