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Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome

Nature Genetics volume 44, pages 783–787 (2012)Cite this article

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Abstract

Nevus sebaceous is a common congenital cutaneous malformation. Affected individuals may develop benign and malignant secondary tumors in the nevi during life. Schimmelpenning syndrome is characterized by the association of nevus sebaceous with extracutaneous abnormalities. We report that of 65 sebaceous nevi studied, 62 (95%) had mutations in the HRAS gene and 3 (5%) had mutations in the KRAS gene. The HRAS c.37G>C mutation, which results in a p.Gly13Arg substitution, was present in 91% of lesions. Nonlesional tissues from 18 individuals had a wild-type sequence, confirming genetic mosaicism. The HRAS c.37G>C mutation was also found in 8 of 8 associated secondary tumors. Mosaicism for HRAS c.37G>C and KRAS c.35G>A mutations was found in two individuals with Schimmelpenning syndrome. Functional analysis of HRAS c.37G>C mutant cells showed constitutive activation of the MAPK and PI3K-Akt signaling pathways. Our results indicate that nevus sebaceous and Schimmelpenning syndrome are caused by postzygotic HRAS and KRAS mutations. These mutations may predispose individuals to the development of secondary tumors in nevus sebaceous.

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Figure 1: Clinical, histological and molecular analyses of nevus sebaceous.
Figure 2: Clinical manifestations and molecular analysis of Schimmelpenning syndrome in a newborn.
Figure 3: Molecular analysis of a syringocystadenoma papilliferum associated with a nevus sebaceous.
Figure 4: Functional characterization of the HRAS c.37G>C mutation.

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Acknowledgements

This work was supported by the research grant HA 5531/1-2 from the Deutsche Forschungsgemeinschaft to C.H. We thank all subjects who participated in this study and A. Groesser and H. Hafner for their valuable support.

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Authors and Affiliations

  1. Department of Dermatology, University of Regensburg, Regensburg, Germany

    Leopold Groesser, Eva Herschberger, Sebastian Singer, Michael Landthaler & Christian Hafner

  2. Dermatopathology Friedrichshafen, Friedrichshafen, Germany

    Arno Ruetten

  3. Laboratory for Diagnostic Genome Analysis, Leiden University Medical Center, Leiden, The Netherlands

    Claudia Ruivenkamp

  4. Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands

    Enrico Lopriore

  5. Department of Dermatology, Georg August University, Göttingen, Germany

    Markus Zutt

  6. Institute of Human Genetics, University of Regensburg, Regensburg, Germany

    Thomas Langmann

  7. Department of Experimental Immunology of the Eye, Center of Ophthalmology, University of Cologne, Cologne, Germany

    Thomas Langmann

  8. Institute for Medical Microbiology and Hygiene, University of Regensburg, Regensburg, Germany

    Laura Klingseisen & Wulf Schneider-Brachert

  9. Servei de Dermatologia, Hospital del Mar-Parc de Salut Mar, Universitat Autònoma de Barcelona, Barcelona, Spain

    Agusti Toll

  10. Grupo de Carcinogénesis Epitelial, Programa de Patología Molecular, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain

    Francisco X Real

  11. Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain

    Francisco X Real

Authors
  1. Leopold Groesser
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  2. Eva Herschberger
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  12. Francisco X Real
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  13. Michael Landthaler
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Contributions

L.G. collected study material, performed microdissection, supervised functional analyses, analyzed and discussed the data and participated in writing the manuscript. E.H. performed microdissection, genetic analyses, cell culture, protein blots and assays and analyzed the data. A.R., C.R., E.L. and M.Z. contributed material and discussed the data. T.L. was involved in the functional characterization of the mutation and discussed the data. S.S., A.T. and M.L. analyzed and discussed the data. L.K. and W.S.-B. contributed to transfection experiments and analyzed the data. F.X.R. analyzed and discussed the data and participated in writing the manuscript. C.H. designed the study, collected study material, supervised all experimental work, analyzed and discussed the data, obtained financial support and wrote the manuscript. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Christian Hafner.

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The authors declare no competing financial interests.

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Supplementary Tables 1 and 2; Supplementary Figure 1 (PDF 192 kb)

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Groesser, L., Herschberger, E., Ruetten, A. et al. Postzygotic HRAS and KRAS mutations cause nevus sebaceous and Schimmelpenning syndrome. Nat Genet 44, 783–787 (2012). https://doi.org/10.1038/ng.2316

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