, Volume 21, Issue 2, pp 287–298 | Cite as

Somatic NRAS mutation in patient with generalized lymphatic anomaly

  • Eugenia Manevitz-Mendelson
  • Gil S. Leichner
  • Ortal Barel
  • Inbal Davidi-Avrahami
  • Limor Ziv-Strasser
  • Eran Eyal
  • Itai Pessach
  • Uri Rimon
  • Aviv Barzilai
  • Abraham Hirshberg
  • Keren Chechekes
  • Ninette Amariglio
  • Gideon Rechavi
  • Karina Yaniv
  • Shoshana GreenbergerEmail author
Original Paper


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.


Lymphangiomatosis NRAS Mutation 



Lymphatic endothelial cells


Human dermal lymphatic endothelial cells


Lymphangiomatosis endothelial cells


Endothelial clls


Mammalian target of rapamycin


Vascular endothelial growth factor A


Whole exome sequencing



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).

Authors’ contribution

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.

Compliance with ethical standards

Ethical approval

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.

Supplementary material

10456_2018_9595_MOESM1_ESM.pdf (2.1 mb)
Supplementary material 1 (PDF 2113 kb)


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Copyright information

© Springer Science+Business Media B.V., part of Springer Nature 2018

Authors and Affiliations

  • Eugenia Manevitz-Mendelson
    • 1
  • Gil S. Leichner
    • 1
  • Ortal Barel
    • 3
  • Inbal Davidi-Avrahami
    • 4
  • Limor Ziv-Strasser
    • 3
  • Eran Eyal
    • 3
  • Itai Pessach
    • 5
    • 2
  • Uri Rimon
    • 6
  • Aviv Barzilai
    • 1
    • 2
  • Abraham Hirshberg
    • 7
  • Keren Chechekes
    • 3
  • Ninette Amariglio
    • 2
    • 3
  • Gideon Rechavi
    • 2
    • 3
  • Karina Yaniv
    • 4
  • Shoshana Greenberger
    • 1
    • 2
    Email author
  1. 1.Department of DermatologySheba Medical CenterTel Hashomer, Ramat GanIsrael
  2. 2.Sackler School of MedicineTel Aviv UniversityTel AvivIsrael
  3. 3.Sheba Cancer Research CenterSheba Medical CenterTel Hashomer, Ramat GanIsrael
  4. 4.Department of Biological RegulationWeizmann Institute of ScienceRehovotIsrael
  5. 5.Department of Pediatric Critical Care, Safra Children’s HospitalSheba Medical CenterTel Hashomer, Ramat GanIsrael
  6. 6.Department of RadiologySheba Medical CenterTel Hashomer, Ramat GanIsrael
  7. 7.Department of Oral Pathology and Oral Medicine, School of Dental MedicineTel-Aviv UniversityTel AvivIsrael

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