Research ArticleGeneticsVascular biology Open Access | 10.1172/JCI173586

Pascal Brouillard,1 Aino Murtomäki,2,3 Veli-Matti Leppänen,2,3 Marko Hyytiäinen,2,3 Sandrine Mestre,4 Lucas Potier,1 Laurence M. Boon,1,5 Nicole Revencu,6 Arin Greene,7 Andrey Anisimov,2,3 Miia H. Salo,8 Reetta Hinttala,8 Lauri Eklund,9 Isabelle Quéré,4 Kari Alitalo,2,3 and Miikka Vikkula1,10

1Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium.

2Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland.

3Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

4Department of Vascular Medicine, Centre de Référence des Maladies Lymphatiques et Vasculaires Rares, Inserm IDESP, CHU Montpellier, Université de Montpellier, Montpellier, France.

5Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, University of Louvain, VASCERN-VASCA Reference Centre, Brussels, Belgium.

6Center for Human Genetics, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium.

7Department of Plastic and Oral Surgery, Lymphedema Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

8Biocenter Oulu, Research Unit of Clinical Medicine and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.

9Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.

10WELBIO department, WEL Research Institute, Wavre, Belgium.

Address correspondence to: Miikka Vikkula, Human Molecular Genetics, de Duve Institute & UCLouvain, Avenue Hippocrate 74, 1200 Brussels, Belgium. Phone: 32.2.7647496; Email: miikka.vikkula@uclouvain.be. Or to: Kari Alitalo, Wihuri Research Institute and Can-Pro Program, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014 University of Helsinki, Finland. Phone: 358.2.941.25511; Email: kari.alitalo@helsinki.fi.

Authorship note: PB, AM, and VML contributed equally to this work. KA and MV contributed equally to this work.

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1Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium.

2Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland.

3Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

4Department of Vascular Medicine, Centre de Référence des Maladies Lymphatiques et Vasculaires Rares, Inserm IDESP, CHU Montpellier, Université de Montpellier, Montpellier, France.

5Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, University of Louvain, VASCERN-VASCA Reference Centre, Brussels, Belgium.

6Center for Human Genetics, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium.

7Department of Plastic and Oral Surgery, Lymphedema Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

8Biocenter Oulu, Research Unit of Clinical Medicine and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.

9Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.

10WELBIO department, WEL Research Institute, Wavre, Belgium.

Address correspondence to: Miikka Vikkula, Human Molecular Genetics, de Duve Institute & UCLouvain, Avenue Hippocrate 74, 1200 Brussels, Belgium. Phone: 32.2.7647496; Email: miikka.vikkula@uclouvain.be. Or to: Kari Alitalo, Wihuri Research Institute and Can-Pro Program, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014 University of Helsinki, Finland. Phone: 358.2.941.25511; Email: kari.alitalo@helsinki.fi.

Authorship note: PB, AM, and VML contributed equally to this work. KA and MV contributed equally to this work.

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1Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium.

2Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland.

3Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

4Department of Vascular Medicine, Centre de Référence des Maladies Lymphatiques et Vasculaires Rares, Inserm IDESP, CHU Montpellier, Université de Montpellier, Montpellier, France.

5Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, University of Louvain, VASCERN-VASCA Reference Centre, Brussels, Belgium.

6Center for Human Genetics, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium.

7Department of Plastic and Oral Surgery, Lymphedema Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

8Biocenter Oulu, Research Unit of Clinical Medicine and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.

9Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.

10WELBIO department, WEL Research Institute, Wavre, Belgium.

Address correspondence to: Miikka Vikkula, Human Molecular Genetics, de Duve Institute & UCLouvain, Avenue Hippocrate 74, 1200 Brussels, Belgium. Phone: 32.2.7647496; Email: miikka.vikkula@uclouvain.be. Or to: Kari Alitalo, Wihuri Research Institute and Can-Pro Program, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014 University of Helsinki, Finland. Phone: 358.2.941.25511; Email: kari.alitalo@helsinki.fi.

Authorship note: PB, AM, and VML contributed equally to this work. KA and MV contributed equally to this work.

Find articles by Leppänen, V. in: JCI | PubMed | Google Scholar |

1Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium.

2Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland.

3Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

4Department of Vascular Medicine, Centre de Référence des Maladies Lymphatiques et Vasculaires Rares, Inserm IDESP, CHU Montpellier, Université de Montpellier, Montpellier, France.

5Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, University of Louvain, VASCERN-VASCA Reference Centre, Brussels, Belgium.

6Center for Human Genetics, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium.

7Department of Plastic and Oral Surgery, Lymphedema Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

8Biocenter Oulu, Research Unit of Clinical Medicine and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.

9Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.

10WELBIO department, WEL Research Institute, Wavre, Belgium.

Address correspondence to: Miikka Vikkula, Human Molecular Genetics, de Duve Institute & UCLouvain, Avenue Hippocrate 74, 1200 Brussels, Belgium. Phone: 32.2.7647496; Email: miikka.vikkula@uclouvain.be. Or to: Kari Alitalo, Wihuri Research Institute and Can-Pro Program, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014 University of Helsinki, Finland. Phone: 358.2.941.25511; Email: kari.alitalo@helsinki.fi.

Authorship note: PB, AM, and VML contributed equally to this work. KA and MV contributed equally to this work.

Find articles by Hyytiäinen, M. in: JCI | PubMed | Google Scholar

1Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium.

2Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland.

3Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

4Department of Vascular Medicine, Centre de Référence des Maladies Lymphatiques et Vasculaires Rares, Inserm IDESP, CHU Montpellier, Université de Montpellier, Montpellier, France.

5Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, University of Louvain, VASCERN-VASCA Reference Centre, Brussels, Belgium.

6Center for Human Genetics, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium.

7Department of Plastic and Oral Surgery, Lymphedema Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

8Biocenter Oulu, Research Unit of Clinical Medicine and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.

9Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.

10WELBIO department, WEL Research Institute, Wavre, Belgium.

Address correspondence to: Miikka Vikkula, Human Molecular Genetics, de Duve Institute & UCLouvain, Avenue Hippocrate 74, 1200 Brussels, Belgium. Phone: 32.2.7647496; Email: miikka.vikkula@uclouvain.be. Or to: Kari Alitalo, Wihuri Research Institute and Can-Pro Program, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014 University of Helsinki, Finland. Phone: 358.2.941.25511; Email: kari.alitalo@helsinki.fi.

Authorship note: PB, AM, and VML contributed equally to this work. KA and MV contributed equally to this work.

Find articles by Mestre, S. in: JCI | PubMed | Google Scholar

1Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium.

2Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland.

3Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

4Department of Vascular Medicine, Centre de Référence des Maladies Lymphatiques et Vasculaires Rares, Inserm IDESP, CHU Montpellier, Université de Montpellier, Montpellier, France.

5Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, University of Louvain, VASCERN-VASCA Reference Centre, Brussels, Belgium.

6Center for Human Genetics, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium.

7Department of Plastic and Oral Surgery, Lymphedema Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

8Biocenter Oulu, Research Unit of Clinical Medicine and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.

9Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.

10WELBIO department, WEL Research Institute, Wavre, Belgium.

Address correspondence to: Miikka Vikkula, Human Molecular Genetics, de Duve Institute & UCLouvain, Avenue Hippocrate 74, 1200 Brussels, Belgium. Phone: 32.2.7647496; Email: miikka.vikkula@uclouvain.be. Or to: Kari Alitalo, Wihuri Research Institute and Can-Pro Program, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014 University of Helsinki, Finland. Phone: 358.2.941.25511; Email: kari.alitalo@helsinki.fi.

Authorship note: PB, AM, and VML contributed equally to this work. KA and MV contributed equally to this work.

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1Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium.

2Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland.

3Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

4Department of Vascular Medicine, Centre de Référence des Maladies Lymphatiques et Vasculaires Rares, Inserm IDESP, CHU Montpellier, Université de Montpellier, Montpellier, France.

5Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, University of Louvain, VASCERN-VASCA Reference Centre, Brussels, Belgium.

6Center for Human Genetics, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium.

7Department of Plastic and Oral Surgery, Lymphedema Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

8Biocenter Oulu, Research Unit of Clinical Medicine and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.

9Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.

10WELBIO department, WEL Research Institute, Wavre, Belgium.

Address correspondence to: Miikka Vikkula, Human Molecular Genetics, de Duve Institute & UCLouvain, Avenue Hippocrate 74, 1200 Brussels, Belgium. Phone: 32.2.7647496; Email: miikka.vikkula@uclouvain.be. Or to: Kari Alitalo, Wihuri Research Institute and Can-Pro Program, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014 University of Helsinki, Finland. Phone: 358.2.941.25511; Email: kari.alitalo@helsinki.fi.

Authorship note: PB, AM, and VML contributed equally to this work. KA and MV contributed equally to this work.

Find articles by Boon, L. in: JCI | PubMed | Google Scholar |

1Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium.

2Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland.

3Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

4Department of Vascular Medicine, Centre de Référence des Maladies Lymphatiques et Vasculaires Rares, Inserm IDESP, CHU Montpellier, Université de Montpellier, Montpellier, France.

5Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, University of Louvain, VASCERN-VASCA Reference Centre, Brussels, Belgium.

6Center for Human Genetics, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium.

7Department of Plastic and Oral Surgery, Lymphedema Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

8Biocenter Oulu, Research Unit of Clinical Medicine and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.

9Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.

10WELBIO department, WEL Research Institute, Wavre, Belgium.

Address correspondence to: Miikka Vikkula, Human Molecular Genetics, de Duve Institute & UCLouvain, Avenue Hippocrate 74, 1200 Brussels, Belgium. Phone: 32.2.7647496; Email: miikka.vikkula@uclouvain.be. Or to: Kari Alitalo, Wihuri Research Institute and Can-Pro Program, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014 University of Helsinki, Finland. Phone: 358.2.941.25511; Email: kari.alitalo@helsinki.fi.

Authorship note: PB, AM, and VML contributed equally to this work. KA and MV contributed equally to this work.

Find articles by Revencu, N. in: JCI | PubMed | Google Scholar

1Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium.

2Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland.

3Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

4Department of Vascular Medicine, Centre de Référence des Maladies Lymphatiques et Vasculaires Rares, Inserm IDESP, CHU Montpellier, Université de Montpellier, Montpellier, France.

5Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, University of Louvain, VASCERN-VASCA Reference Centre, Brussels, Belgium.

6Center for Human Genetics, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium.

7Department of Plastic and Oral Surgery, Lymphedema Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

8Biocenter Oulu, Research Unit of Clinical Medicine and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.

9Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.

10WELBIO department, WEL Research Institute, Wavre, Belgium.

Address correspondence to: Miikka Vikkula, Human Molecular Genetics, de Duve Institute & UCLouvain, Avenue Hippocrate 74, 1200 Brussels, Belgium. Phone: 32.2.7647496; Email: miikka.vikkula@uclouvain.be. Or to: Kari Alitalo, Wihuri Research Institute and Can-Pro Program, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014 University of Helsinki, Finland. Phone: 358.2.941.25511; Email: kari.alitalo@helsinki.fi.

Authorship note: PB, AM, and VML contributed equally to this work. KA and MV contributed equally to this work.

Find articles by Greene, A. in: JCI | PubMed | Google Scholar

1Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium.

2Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland.

3Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

4Department of Vascular Medicine, Centre de Référence des Maladies Lymphatiques et Vasculaires Rares, Inserm IDESP, CHU Montpellier, Université de Montpellier, Montpellier, France.

5Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, University of Louvain, VASCERN-VASCA Reference Centre, Brussels, Belgium.

6Center for Human Genetics, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium.

7Department of Plastic and Oral Surgery, Lymphedema Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

8Biocenter Oulu, Research Unit of Clinical Medicine and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.

9Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.

10WELBIO department, WEL Research Institute, Wavre, Belgium.

Address correspondence to: Miikka Vikkula, Human Molecular Genetics, de Duve Institute & UCLouvain, Avenue Hippocrate 74, 1200 Brussels, Belgium. Phone: 32.2.7647496; Email: miikka.vikkula@uclouvain.be. Or to: Kari Alitalo, Wihuri Research Institute and Can-Pro Program, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014 University of Helsinki, Finland. Phone: 358.2.941.25511; Email: kari.alitalo@helsinki.fi.

Authorship note: PB, AM, and VML contributed equally to this work. KA and MV contributed equally to this work.

Find articles by Anisimov, A. in: JCI | PubMed | Google Scholar |

1Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium.

2Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland.

3Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

4Department of Vascular Medicine, Centre de Référence des Maladies Lymphatiques et Vasculaires Rares, Inserm IDESP, CHU Montpellier, Université de Montpellier, Montpellier, France.

5Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, University of Louvain, VASCERN-VASCA Reference Centre, Brussels, Belgium.

6Center for Human Genetics, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium.

7Department of Plastic and Oral Surgery, Lymphedema Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

8Biocenter Oulu, Research Unit of Clinical Medicine and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.

9Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.

10WELBIO department, WEL Research Institute, Wavre, Belgium.

Address correspondence to: Miikka Vikkula, Human Molecular Genetics, de Duve Institute & UCLouvain, Avenue Hippocrate 74, 1200 Brussels, Belgium. Phone: 32.2.7647496; Email: miikka.vikkula@uclouvain.be. Or to: Kari Alitalo, Wihuri Research Institute and Can-Pro Program, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014 University of Helsinki, Finland. Phone: 358.2.941.25511; Email: kari.alitalo@helsinki.fi.

Authorship note: PB, AM, and VML contributed equally to this work. KA and MV contributed equally to this work.

Find articles by Salo, M. in: JCI | PubMed | Google Scholar |

1Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium.

2Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland.

3Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

4Department of Vascular Medicine, Centre de Référence des Maladies Lymphatiques et Vasculaires Rares, Inserm IDESP, CHU Montpellier, Université de Montpellier, Montpellier, France.

5Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, University of Louvain, VASCERN-VASCA Reference Centre, Brussels, Belgium.

6Center for Human Genetics, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium.

7Department of Plastic and Oral Surgery, Lymphedema Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

8Biocenter Oulu, Research Unit of Clinical Medicine and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.

9Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.

10WELBIO department, WEL Research Institute, Wavre, Belgium.

Address correspondence to: Miikka Vikkula, Human Molecular Genetics, de Duve Institute & UCLouvain, Avenue Hippocrate 74, 1200 Brussels, Belgium. Phone: 32.2.7647496; Email: miikka.vikkula@uclouvain.be. Or to: Kari Alitalo, Wihuri Research Institute and Can-Pro Program, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014 University of Helsinki, Finland. Phone: 358.2.941.25511; Email: kari.alitalo@helsinki.fi.

Authorship note: PB, AM, and VML contributed equally to this work. KA and MV contributed equally to this work.

Find articles by Hinttala, R. in: JCI | PubMed | Google Scholar

1Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium.

2Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland.

3Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

4Department of Vascular Medicine, Centre de Référence des Maladies Lymphatiques et Vasculaires Rares, Inserm IDESP, CHU Montpellier, Université de Montpellier, Montpellier, France.

5Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, University of Louvain, VASCERN-VASCA Reference Centre, Brussels, Belgium.

6Center for Human Genetics, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium.

7Department of Plastic and Oral Surgery, Lymphedema Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

8Biocenter Oulu, Research Unit of Clinical Medicine and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.

9Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.

10WELBIO department, WEL Research Institute, Wavre, Belgium.

Address correspondence to: Miikka Vikkula, Human Molecular Genetics, de Duve Institute & UCLouvain, Avenue Hippocrate 74, 1200 Brussels, Belgium. Phone: 32.2.7647496; Email: miikka.vikkula@uclouvain.be. Or to: Kari Alitalo, Wihuri Research Institute and Can-Pro Program, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014 University of Helsinki, Finland. Phone: 358.2.941.25511; Email: kari.alitalo@helsinki.fi.

Authorship note: PB, AM, and VML contributed equally to this work. KA and MV contributed equally to this work.

Find articles by Eklund, L. in: JCI | PubMed | Google Scholar

1Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium.

2Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland.

3Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

4Department of Vascular Medicine, Centre de Référence des Maladies Lymphatiques et Vasculaires Rares, Inserm IDESP, CHU Montpellier, Université de Montpellier, Montpellier, France.

5Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, University of Louvain, VASCERN-VASCA Reference Centre, Brussels, Belgium.

6Center for Human Genetics, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium.

7Department of Plastic and Oral Surgery, Lymphedema Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

8Biocenter Oulu, Research Unit of Clinical Medicine and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.

9Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.

10WELBIO department, WEL Research Institute, Wavre, Belgium.

Address correspondence to: Miikka Vikkula, Human Molecular Genetics, de Duve Institute & UCLouvain, Avenue Hippocrate 74, 1200 Brussels, Belgium. Phone: 32.2.7647496; Email: miikka.vikkula@uclouvain.be. Or to: Kari Alitalo, Wihuri Research Institute and Can-Pro Program, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014 University of Helsinki, Finland. Phone: 358.2.941.25511; Email: kari.alitalo@helsinki.fi.

Authorship note: PB, AM, and VML contributed equally to this work. KA and MV contributed equally to this work.

Find articles by Quéré, I. in: JCI | PubMed | Google Scholar

1Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium.

2Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland.

3Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

4Department of Vascular Medicine, Centre de Référence des Maladies Lymphatiques et Vasculaires Rares, Inserm IDESP, CHU Montpellier, Université de Montpellier, Montpellier, France.

5Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, University of Louvain, VASCERN-VASCA Reference Centre, Brussels, Belgium.

6Center for Human Genetics, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium.

7Department of Plastic and Oral Surgery, Lymphedema Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

8Biocenter Oulu, Research Unit of Clinical Medicine and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.

9Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.

10WELBIO department, WEL Research Institute, Wavre, Belgium.

Address correspondence to: Miikka Vikkula, Human Molecular Genetics, de Duve Institute & UCLouvain, Avenue Hippocrate 74, 1200 Brussels, Belgium. Phone: 32.2.7647496; Email: miikka.vikkula@uclouvain.be. Or to: Kari Alitalo, Wihuri Research Institute and Can-Pro Program, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014 University of Helsinki, Finland. Phone: 358.2.941.25511; Email: kari.alitalo@helsinki.fi.

Authorship note: PB, AM, and VML contributed equally to this work. KA and MV contributed equally to this work.

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1Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium.

2Wihuri Research Institute, Biomedicum Helsinki, Helsinki, Finland.

3Translational Cancer Medicine Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

4Department of Vascular Medicine, Centre de Référence des Maladies Lymphatiques et Vasculaires Rares, Inserm IDESP, CHU Montpellier, Université de Montpellier, Montpellier, France.

5Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires Saint-Luc, University of Louvain, VASCERN-VASCA Reference Centre, Brussels, Belgium.

6Center for Human Genetics, Cliniques Universitaires Saint-Luc, University of Louvain, Brussels, Belgium.

7Department of Plastic and Oral Surgery, Lymphedema Program, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

8Biocenter Oulu, Research Unit of Clinical Medicine and Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland.

9Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, Biocenter Oulu, University of Oulu, Oulu, Finland.

10WELBIO department, WEL Research Institute, Wavre, Belgium.

Address correspondence to: Miikka Vikkula, Human Molecular Genetics, de Duve Institute & UCLouvain, Avenue Hippocrate 74, 1200 Brussels, Belgium. Phone: 32.2.7647496; Email: miikka.vikkula@uclouvain.be. Or to: Kari Alitalo, Wihuri Research Institute and Can-Pro Program, Biomedicum Helsinki, PO Box 63 (Haartmaninkatu 8), FI-00014 University of Helsinki, Finland. Phone: 358.2.941.25511; Email: kari.alitalo@helsinki.fi.

Authorship note: PB, AM, and VML contributed equally to this work. KA and MV contributed equally to this work.

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Authorship note: PB, AM, and VML contributed equally to this work. KA and MV contributed equally to this work.

Published May 31, 2024 - More info

Published in Volume 134, Issue 14 on July 15, 2024
J Clin Invest. 2024;134(14):e173586. https://doi.org/10.1172/JCI173586.
© 2024 Brouillard et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published May 31, 2024 - Version history
Received: July 3, 2023; Accepted: May 24, 2024 View PDF Abstract

Primary lymphedema (PL), characterized by tissue swelling, fat accumulation, and fibrosis, results from defects in lymphatic vessels or valves caused by mutations in genes involved in development, maturation, and function of the lymphatic vascular system. Pathogenic variants in various genes have been identified in about 30% of PL cases. By screening of a cohort of 755 individuals with PL, we identified two TIE1 (tyrosine kinase with immunoglobulin- and epidermal growth factor–like domains 1) missense variants and one truncating variant, all predicted to be pathogenic by bioinformatic algorithms. The TIE1 receptor, in complex with TIE2, binds angiopoietins to regulate the formation and remodeling of blood and lymphatic vessels. The premature stop codon mutant encoded an inactive truncated extracellular TIE1 fragment with decreased mRNA stability, and the amino acid substitutions led to decreased TIE1 signaling activity. By reproducing the two missense variants in mouse Tie1 via CRISPR/Cas9, we showed that both cause edema and are lethal in homozygous mice. Thus, our results indicate that TIE1 loss-of-function variants can cause lymphatic dysfunction in patients. Together with our earlier demonstration that ANGPT2 loss-of-function mutations can also cause PL, our results emphasize the important role of the ANGPT2/TIE1 pathway in lymphatic function.

Graphical Abstract Introduction

The pathogenesis of primary lymphedema (PL) results from defective development and/or function of the lymphatic system (ref. 1; reviewed in refs. 2–5). PL is characterized by accumulation of interstitial lymph, mostly in the limbs, but PL can also affect other parts of the body, and with time, PL results in increased fat accumulation, inflammation, and fibrosis. PL can develop in utero and be congenital, such as in Nonne-Milroy disease caused by VEGFR3 (FLT4 gene) mutations (6, 7), but it can also appear later in life, during puberty or adulthood, such as in patients with EPHB4-related PL (8). In lymphoscintigraphy, the lymphatic system in PL seems most often hypoplastic, but it can also be hyperplastic.

Thirty-three genes or loci have been shown to cause PL, as evidenced by cosegregation of variants in several pedigrees, and/or by results from complementary functional in vitro and/or in vivo analysis (2, 9, 10). Variants in another 22 genes have been suggested to be causal, but without formal proof (2, 11). Originally centered around the VEGFC/VEGFR3 signaling pathway (1, 7, 12), mutations in additional ligand-receptor families have emerged as causes of PL.

The ANGPT/TIE ligand-receptor signaling pathway is necessary for blood and lymphatic vessel remodeling during embryonic and postnatal development, and for maintenance of the mature vasculature (13–15). Angiopoietin-1 (ANGPT1) is the primary multimeric agonist that binds to the TIE2 (tyrosine kinase with immunoglobulin- and epidermal growth factor–like domains 2) extracellular domain, causing receptor clustering and activation (16–18). Deletion of the mouse Angpt1 gene is lethal in embryos (17). The second ligand, ANGPT2, mainly produced by endothelial cells, functions as an autocrine TIE2 antagonist or agonist, depending on the context (19–21). Angpt2 gene deletion is compatible with embryonic vascular development but subsequently results in abnormal angiogenic remodeling and defective lymphatic vessels (22). Deletion of the third angiopoietin (Angpt4) in mice results in defective venous maturation in the retina (23), and combined deletion of Angpt2 and Angpt4 in a hypomorphic Schlemm’s canal (lymphatic-like vessel in the anterior part of the eye) and glaucomatous changes in the eyes (24).

The function of TIE1, discovered in 1992, is still poorly understood (25). TIE1 does not bind angiopoietins, yet both TIE1 and TIE2 are required for the development of embryonic blood and lymphatic vessels in mice (26–29). Vasculature in Tie1-deficient embryos fails to mature, resulting in embryonic death during late gestation (30, 31). Notably, homozygous deletion of mouse Tie1 was shown to impair the development of lymphatic vessels and Schlemm’s canal, resulting in elevated intraocular pressure (26, 32). In adult mice, TIE1 regulates TIE2 in angiogenic tip cells and sustains TIE2 signaling in the remodeling stalk cells in the vasculature (33). TIE1 and TIE2 are also involved in vascular pathologies, including atherosclerosis and tumor angiogenesis (34–37).

TIE1 is capable of modulating TIE2 activity in a context-dependent manner by forming TIE1/TIE2 heteromers. Angiopoietin ligands and designed angiopoietin variants, such as pentameric Comp-ANGPT1, induce TIE1 phosphorylation in a TIE2-dependent manner (18, 38–40). Binding of an agonistic ligand to TIE2 activates a number of intracellular signaling pathways, notably the PI3K (phosphoinositide 3-kinase)/AKT, MAPK (mitogen-activated protein kinase), and DOK-R pathways (41–43). In contrast, the contribution of TIE1 in ANGPT signaling is incompletely understood. TIE1 is essential for the agonistic activity of ANGPT1 and the autocrine activity of ANGPT2 on TIE2, as its deletion from endothelium in adult mice reduced TIE2 phosphorylation and downstream AKT activation (40). Cleavage of the ectodomain of TIE1 promoted by inflammation was associated with a switch of ANGPT2 from a TIE2 agonist to an antagonist (40, 44). Furthermore, AKT activation mediated by autocrine ANGPT2 and TIE1 was required for expression of VEGFR3 on lymphatic endothelial cell surface, as well as for VEGFC-induced lymphangiogenesis in adult mice (45).

Genetic variants of components belonging to the ANGPT/TIE receptor signaling pathway have been associated with several diseases. Gain-of-function mutations in TIE2 (gene TEK) underlie inherited venous malformations (VMCM) (46), whereas TIE2 loss-of-function mutations cause primary congenital glaucoma (PCG) (47). Somatic gain-of-function TIE2 mutations are associated with sporadic venous malformations, blue rubber bleb nevus syndrome (48), and multifocal sporadic venous malformations (48, 49). Pathogenic ANGPT1 variants have been linked to hereditary angioedema and primary glaucoma (50, 51). We recently demonstrated that a heterozygous ANGPT2 deletion and 3 pathogenic variants that result in loss of function of ANGPT2 cause autosomal dominant PL (21), whereas another heterozygous ANGPT2 amino acid substitution caused instead a gain of function that led to cutaneous lymphatic hyperplasia (21). More recently, we also linked a biallelic ANGPT2 loss-of-function v