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Recessive primary congenital lymphoedema caused by a VEGFR3 mutation
  1. Arash Ghalamkarpour (arash.ghalamkarpour{at}uclouvain.be)
  1. Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Belgium
    1. Wolfgang Holnthoner (wolfgang.holnthoner{at}helsinki.fi)
    1. Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki, Finland
      1. Pipsa Saharinen (pipsa.saharinen{at}helsinki.fi)
      1. Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki, Finland
        1. Laurence M Boon (laurence.boon{at}uclouvain.be)
        1. Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Belgium
          1. John B Mulliken (john.mulliken{at}childrens.harvard.edu)
          1. Vascular Anomalies Center, Department of Plastic Surgery, Harvard Medical School, United States
            1. Kari Alitalo (kari.alitalo{at}helsinki.fi)
            1. Molecular/Cancer Biology Laboratory and Ludwig Institute for Cancer Research, Biomedicum Helsinki, Finland
              1. Miikka Vikkula (miikka.vikkula{at}uclouvain.be)
              1. Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Belgium

                Abstract

                Background: Heterozygous mutations in VEGFR3 have been identified in some familial cases with dominantly inherited primary congenital lymphoedema, known as Nonne-Milroy disease. Recessive cases of primary lymphoedema with a genetic cause are not known, except for two families with syndromic hypotrichosis-lymphoedema-telangiectasia, with a SOX18 mutation.

                Results: In this study, we present the first case of isolated primary congenital lymphoedema with recessive inheritance, caused by a homozygous mutation in VEGFR3. The novel mutation is a transition from alanine-to-threonine in amino acid 855, located in the ATP binding domain of the VEGFR3 receptor. Assessment of receptor function showed impaired ligand-induced internalization and ERK1/2 activity. Moreover, receptor phosphorylation was reduced, although, less so than for a kinase-dead VEGFR3 mutation, which causes Nonne-Milroy disease.

                Conclusion: A hypomorphic VEGFR3 mutation, with moderate effect on receptor function, in a homozygous state can result in insufficient lymphatic functioning. Thus, in addition to Nonne-Milroy disease with dominant inheritance, VEGFR3 alterations can cause isolated recessive primary congenital lymphoedema. These data expand our understanding of the aetiology of congenital lymphoedema and suggest that large sale screening of VEGFR3 in all primary lymphoedema patients is necessary.

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