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Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome

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Abstract

Cardio-facio-cutaneous (CFC) syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. It phenotypically overlaps with Noonan and Costello syndrome, which are caused by mutations in PTPN11 and HRAS, respectively. In 43 individuals with CFC, we identified two heterozygous KRAS mutations in three individuals and eight BRAF mutations in 16 individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the three related disorders.

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Figure 1: Mutations in KRAS and BRAF were identified in individuals with CFC syndrome.

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Acknowledgements

We wish to thank the individuals and their families who participated in this study and the doctors who referred the cases. The support of CFC International in facilitating the collection of patient samples is gratefully acknowledged. We are grateful to J. Miyazaki, Osaka University, for supplying the pCAGGS expression vector. This work was supported by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan and Grants-in-Aid from the Ministry of Health, Labor, and Welfare of Japan.

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Authors and Affiliations

  1. Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan

    Tetsuya Niihori, Yoko Aoki, Yoko Narumi, Kumi Kato, Shigeo Kure & Yoichi Matsubara

  2. Università Cattolica, Istituto di Genetica Medica, Rome, Italy

    Giovanni Neri

  3. Department of Genetics, Hôpital Robert Debré (APHP), Paris, France

    Hélène Cavé, Alain Verloes & Clarisse Baumann

  4. Department of Planning and Research, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan

    Nobuhiko Okamoto

  5. Clinical and Molecular Genetics Unit, Institute of Child Health, London, UK

    Raoul C M Hennekam

  6. Department of Pediatrics, Academic Medical Center, Amsterdam, The Netherlands

    Raoul C M Hennekam

  7. Institut für Humangenetik, Universität Essen, Essen, Germany

    Gabriele Gillessen-Kaesbach & Dagmar Wieczorek

  8. Medical Genetics Center, Federal University of Sao Paulo (UNIFESP), Sao Paulo, Brazil

    Maria Ines Kavamura

  9. Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan

    Kenji Kurosawa

  10. Division of Medical Genetics, Saitama Children's Medical Center, Saitama, Japan

    Hirofumi Ohashi

  11. Great Ormond Street Hospital, London, UK

    Louise Wilson

  12. Genetic Department, Pitie-Salpetriere University Hospital, Paris, France

    Delphine Heron

  13. Genetic Department, University Hospital, Angers, France

    Dominique Bonneau

  14. Dipartimento di Scienze Pediatriche Mediche e Chirurgiche, Unità Operativa Complessa Patologia Neonatale e Terapia Intensiva, Azienda Ospedaliera Universitaria G. Martino, Messina, Italy

    Giuseppina Corona

  15. Department of Medical Genetics, University of the Ryukyus School of Medicine, Okinawa, Japan

    Tadashi Kaname & Kenji Naritomi

  16. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokahama, Japan

    Naomichi Matsumoto

  17. Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation, 21st Century COE Program, Tohoku University, Sendai, Japan

    Kumi Kato & Yoichi Matsubara

Authors
  1. Tetsuya Niihori
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  2. Yoko Aoki
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  3. Yoko Narumi
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  4. Giovanni Neri
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  5. Hélène Cavé
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  6. Alain Verloes
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  7. Nobuhiko Okamoto
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  8. Raoul C M Hennekam
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  9. Gabriele Gillessen-Kaesbach
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  10. Dagmar Wieczorek
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  11. Maria Ines Kavamura
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  12. Kenji Kurosawa
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  13. Hirofumi Ohashi
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  14. Louise Wilson
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  15. Delphine Heron
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  16. Dominique Bonneau
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  17. Giuseppina Corona
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  18. Tadashi Kaname
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  19. Kenji Naritomi
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  20. Clarisse Baumann
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  21. Naomichi Matsumoto
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  22. Kumi Kato
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  23. Shigeo Kure
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  24. Yoichi Matsubara
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Corresponding author

Correspondence to Yoko Aoki.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

KRAS gene mutations identified in CFC syndrome. (PDF 762 kb)

Supplementary Fig. 2

BRAF mutations in five families. (PDF 522 kb)

Supplementary Fig. 3

Stimulation of ELK transcription in KRAS and BRAF mutations. (PDF 28 kb)

Supplementary Fig. 4

Crystal structure of the BRAF kinase domain and mutations identified in individuals with CFC. (PDF 988 kb)

Supplementary Table 1

Summary of clinical features of individuals with CFC with mutations. (PDF 39 kb)

Supplementary Table 2

Comparison between individuals with KRAS and BRAF mutations with respect to clinical manifestations. (PDF 56 kb)

Supplementary Table 3

Clinical features of 19 CFC individuals with mutations. (PDF 112 kb)

Supplementary Methods (PDF 87 kb)

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Niihori, T., Aoki, Y., Narumi, Y. et al. Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome. Nat Genet 38, 294–296 (2006). https://doi.org/10.1038/ng1749

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  • DOI: https://doi.org/10.1038/ng1749

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