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Somatic NRAS mutation in patient with generalized lymphatic anomaly

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Abstract

Generalized lymphatic anomaly (GLA or lymphangiomatosis) is a rare disease characterized by a diffuse proliferation of lymphatic vessels in skin and internal organs. It often leads to progressive respiratory failure and death, but its etiology is unknown. Here, we isolated lymphangiomatosis endothelial cells from GLA tissue. These cells were characterized by high proliferation and survival rates, but displayed impaired capacities for migration and tube formation. We employed whole exome sequencing to search for disease-causing genes and identified a somatic mutation in NRAS. We used mouse and zebrafish model systems to initially evaluate the role of this mutation in the development of the lymphatic system, and we studied the effect of drugs blocking the downstream effectors, mTOR and ERK, on this disease.

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Abbreviations

LEC:

Lymphatic endothelial cells

HDLEC:

Human dermal lymphatic endothelial cells

LyECs:

Lymphangiomatosis endothelial cells

EC:

Endothelial clls

MTOR:

Mammalian target of rapamycin

VEGF-A:

Vascular endothelial growth factor A

WES:

Whole exome sequencing

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Acknowledgements

We thank M. Grunspan for help with zebrafish experiments; Sarit Farage-Barhom for her help with bioinformatics analysis; Michael Dellinger, The Lymphatic Malformation Institute (LMI) for fruitful discussions. This project was supported by grants from the Israel Science Foundation (Grant No. 1716/11 to S.G.), Basil O’Connor Starter Scholar Research Award Grant from the March of Dimes (No. 5-FY12-55, to S.G), Marie Curie Re-integration grant (FP7-PEOPLE-2010-IRG to S.G).

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Authors and Affiliations

  1. Department of Dermatology, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel

    Eugenia Manevitz-Mendelson, Gil S. Leichner, Aviv Barzilai & Shoshana Greenberger

  2. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Itai Pessach, Aviv Barzilai, Ninette Amariglio, Gideon Rechavi & Shoshana Greenberger

  3. Sheba Cancer Research Center, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel

    Ortal Barel, Limor Ziv-Strasser, Eran Eyal, Keren Chechekes, Ninette Amariglio & Gideon Rechavi

  4. Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel

    Inbal Davidi-Avrahami & Karina Yaniv

  5. Department of Pediatric Critical Care, Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel

    Itai Pessach

  6. Department of Radiology, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel

    Uri Rimon

  7. Department of Oral Pathology and Oral Medicine, School of Dental Medicine, Tel-Aviv University, Tel Aviv, Israel

    Abraham Hirshberg

Authors
  1. Eugenia Manevitz-Mendelson
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  2. Gil S. Leichner
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Contributions

E.M., G.L., N.A., A.B.,G.R., K.Y., and S.G. designed research studies; E.M., G.L., O.B., I.D., L.S., E.E., A.H., and K.C. conducted experiments and acquired data; E.M., G.L., O.B., I.D., L.S., E.E., I.P., and U.R., A.B., G.R., K.Y., and S.G analyzed and interpreted data; I.P, and U.R. provided human tissue samples; E.M., G.L., G.R., K.Y., and S.G wrote the manuscript.

Corresponding author

Correspondence to Shoshana Greenberger.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

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Manevitz-Mendelson, E., Leichner, G.S., Barel, O. et al. Somatic NRAS mutation in patient with generalized lymphatic anomaly. Angiogenesis 21, 287–298 (2018). https://doi.org/10.1007/s10456-018-9595-8

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