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Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans

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Abstract

Lymphedema, lymphangiectasias, mental retardation and unusual facial characteristics define the autosomal recessive Hennekam syndrome. Homozygosity mapping identified a critical chromosomal region containing CCBE1, the human ortholog of a gene essential for lymphangiogenesis in zebrafish. Homozygous and compound heterozygous mutations in seven subjects paired with functional analysis in a zebrafish model identify CCBE1 as one of few genes causing primary generalized lymph-vessel dysplasia in humans.

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Figure 1: Phenotypes of subjects with generalized lymphatic dysplasia and homozygosity mapping in five subjects with consanguineous parents.
Figure 2: Mutations in CCBE1 abolish normal gene function.

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NCBI Reference Sequence

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Acknowledgements

S.S.-M. and E.G. were supported by the Koninklijke Nederlandse Akademie van Wetenschappen, B.M.H. by an Australian National Health and Medical Research Council CJ Martin Fellowship. M.J. Van De Vijver (Academic Medical Centre Amsterdam) provided gut biopsies of controls and H. Begthel (Hubrecht Institute, Utrecht) performed histology. T. Nilsson (McGill University) generously provided the GalNAc-T2GFP cell line and A. Akhmanova (Erasmus Medical Center, Rotterdam) the NPY:mVenus cell line. We are grateful to the subjects and their families for their cooperation.

Author information

Author notes

  1. Stefan Schulte-Merker and Raoul C Hennekam: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Genetics, Academic Medical Centre, Amsterdam, The Netherlands

    Marielle Alders, Faranak Salehi & Marcel M A M Mannens

  2. Hubrecht Institute – Koninklijke Nederlandse Akademie van Wetenschappen and University Medical Centre, Utrecht, The Netherlands

    Benjamin M Hogan, Evisa Gjini, Merlijn Witte & Stefan Schulte-Merker

  3. Department of Paediatrics and Pathology, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates

    Lihadh Al-Gazali

  4. Department of Clinical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands

    Eric A Hennekam

  5. Department of Medical Genetics, Oslo University Hospital, Rikshospitalet, Oslo, Norway

    Eva E Holmberg & Trine E Prescott

  6. Department of Pediatrics, Free,

    Margot F Mulder

  7. University Medical Center, Amsterdam, The Netherlands

    Margot F Mulder

  8. Department of Pathology, University Medical Centre Utrecht, Utrecht, The Netherlands

    G Johan A Offerhaus

  9. Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands

    G Johan A Offerhaus

  10. Department of Pediatrics Amalia, Isala Clinics, Zwolle, The Netherlands

    Eelco J Schroor

  11. Department of Clinical Genetics, University Medical Centre Groningen, Groningen, The Netherlands

    Joke B G M Verheij

  12. Department of Clinical Genetics, Free University Medical Center, Amsterdam, The Netherlands

    Petra J Zwijnenburg

  13. Laboratory of Human Molecular Genetics, de Duve Institute, Université Catholique de Louvain, Brussels, Belgium

    Mikka Vikkula

  14. Clinical and Molecular Genetics Unit, Institute of Child Health, Great Ormond Street Hospital for Children, University College London, London, UK

    Raoul C Hennekam

  15. Department of Pediatrics, Academic Medical Centre, Amsterdam, The Netherlands

    Petra J Zwijnenburg & Raoul C Hennekam

Authors
  1. Marielle Alders
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  2. Benjamin M Hogan
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  3. Evisa Gjini
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  4. Faranak Salehi
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  5. Lihadh Al-Gazali
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  6. Eric A Hennekam
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  7. Eva E Holmberg
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  8. Marcel M A M Mannens
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  9. Margot F Mulder
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  10. G Johan A Offerhaus
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  11. Trine E Prescott
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  12. Eelco J Schroor
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  13. Joke B G M Verheij
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  14. Merlijn Witte
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  15. Petra J Zwijnenburg
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  16. Mikka Vikkula
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  17. Stefan Schulte-Merker
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  18. Raoul C Hennekam
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Contributions

L.A.-G., E.E.H., M.F.M., T.E.P., E.J.S., J.B.G.M.V., P.J.Z. and R.C.H. analyzed affected individuals, and E.A.H. performed genealogical studies. M.A., F.S., M.M.A.M.M., M.V., B.M.H., E.G., G.J.A.O., M.W. and S.S.-M. carried out experiments and analyzed data. S.S.-M. supervised the zebrafish experiments, and R.C.H. supervised the clinical and molecular studies and initiated the study. M.A., S.S.-M. and R.C.H. wrote the manuscript.

Corresponding author

Correspondence to Raoul C Hennekam.

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Competing interests

The KNAW has filed a patent on human CCBE1.[AU: (i) Spell out KNAW please. (ii) Please specify CCBE1 protein or CCBE1 nucleic acid.]

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6, Supplementary Tables 1–3 and Supplementary Methods (PDF 1339 kb)

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Alders, M., Hogan, B., Gjini, E. et al. Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans. Nat Genet 41, 1272–1274 (2009). https://doi.org/10.1038/ng.484

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  • DOI: https://doi.org/10.1038/ng.484

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