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Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans

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

References

  1. Karpanen, T. & Alitalo, K. Annual Rev. Pathol. Dis. 3, 367–397 (2008).

    Article  CAS  Google Scholar 

  2. Oliver, G. & Alitalo, K. Annu. Rev. Cell Dev. Biol. 21, 457–483 (2005).

    Article  CAS  Google Scholar 

  3. Cueni, L.N. & Detmar, M. J. Invest. Dermatol. 126, 2167–2177 (2006).

    Article  CAS  Google Scholar 

  4. Ferrell, R.E. et al. Hum. Mol. Genet. 7, 2073–2078 (1998).

    Article  CAS  Google Scholar 

  5. Fang, J. et al. Am. J. Hum. Genet. 67, 1382–1388 (2000).

    Article  CAS  Google Scholar 

  6. Irrthum, A. et al. Am. J. Hum. Genet. 72, 1470–1478 (2003).

    Article  CAS  Google Scholar 

  7. Hilliard, R.I., Mckendry, J.B.J. & Phillips, M.J. Pediatrics 86, 988–994 (1990).

    CAS  PubMed  Google Scholar 

  8. Hennekam, R.C. et al. Am. J. Med. Genet. 34, 593–600 (1989).

    Article  CAS  Google Scholar 

  9. Van Balkom, I.D. et al. Am. J. Med. Genet. 112, 412–421 (2002).

    Article  Google Scholar 

  10. Bellini, C. et al. Am. J. Med. Genet. 120A, 92–96 (2003).

    Article  Google Scholar 

  11. Al-Gazali, L.I., Hertecant, J., Ahmed, R., Khan, N.A. & Padmanabhan, R. Clin. Dysmorphol. 12, 227–232 (2003).

    Article  CAS  Google Scholar 

  12. Hogan, B.M. et al. Nat. Genet. 41, 396–398 (2009).

    Article  CAS  Google Scholar 

  13. Maquat, L.E. Rev. Mol. Cell. Biol. 5, 89–99 (2004).

    Article  CAS  Google Scholar 

  14. Yaniv, K. et al. Nat. Med. 12, 711–716 (2006).

    Article  CAS  Google Scholar 

  15. Küchler, A.M. et al. Curr. Biol. 16, 1244–1248 (2006).

    Article  Google Scholar 

Download references

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.

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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.

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Correspondence to Raoul C Hennekam.

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

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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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