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Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia

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Abstract

Sclerosteosis and Van Buchem disease are related recessive sclerosing bone dysplasias caused by alterations in the SOST gene. We tested the hypothesis that craniodiaphyseal dysplasia (CDD) (MIM 122860), an extremely rare sclerosing bone dysplasia resulting facial distortion referred to as “leontiasis ossea”, could also be caused by SOST mutations. We discovered mutations c.61G>A (Val21Met) and c.61G>T (Val21Leu) two children with CDD. As these mutations are located in the secretion signal of the SOST gene, we tested their effect on secretion by transfecting the mutant constructs into 293E cells. Intriguingly, these mutations greatly reduced the secretion of SOST. We conclude that CDD, the most severe form of sclerotic bone disease, is part of a spectrum of disease caused by mutations in SOST. Unlike the other SOST-related conditions, sclerosteosis and Van Buchem disease that are inherited as recessive traits seem to be caused by a dominant negative mechanism.

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Acknowledgments

This study was supported by a grant of the Korea Healthcare technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (A080588) and the Samsung Biomedical Research Institute grant, SBRI C-A9-240-2.

Conflict of interest

The authors have nothing to disclose.

Author information

Authors and Affiliations

  1. Center for Pediatric Oncology, National Cancer Center, Goyang, Korea

    Su Jin Kim

  2. Department of Diagnostic Imaging, Polish Mother’s Memorial Hospital-Reaserch Institute, Lodz, Poland

    Tadeusz Bieganski

  3. Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong, Gangnam-gu, Seoul, 135-710, Korea

    Young Bae Sohn, Sung Won Park & Dong-Kyu Jin

  4. Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    Geung Hwan Ahn & Yoon-La Choi

  5. Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

    Chang-Seok Ki

  6. Department of Medical Imaging, New Children’s Hospital, Sydney, Australia

    Kazimierz Kozlowski

  7. Division of Neuroscience, Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Mikhail Semënov

  8. Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan

    Nobuhiko Okamoto

  9. Clinical Research Center, Samsung Biomedical Research Institute, Seoul, Korea

    Chi Hwa Kim & Ah-Ra Ko

  10. Department of Radiology, Ajou University Hospital, Suwon, Korea

    Ok-Hwa Kim

  11. Department of Radiology, Tokyo Metropolitan Kiyose Children’s Hospital, Tokyo, Japan

    Gen Nishimura

  12. Institute of Human Genetics, University of Freiburg Hospital, Freiburg, Germany

    Sheila Unger

  13. Department of Pediatrics, University of Freiburg Hospital, Freiburg, Germany

    Andrea Superti-Furga

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  1. Su Jin Kim
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  2. Tadeusz Bieganski
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  3. Young Bae Sohn
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  4. Kazimierz Kozlowski
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  6. Nobuhiko Okamoto
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  7. Chi Hwa Kim
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  8. Ah-Ra Ko
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  11. Sung Won Park
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  12. Chang-Seok Ki
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  13. Ok-Hwa Kim
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  14. Gen Nishimura
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  15. Sheila Unger
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  16. Andrea Superti-Furga
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  17. Dong-Kyu Jin
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Corresponding author

Correspondence to Dong-Kyu Jin.

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Kim, S.J., Bieganski, T., Sohn, Y.B. et al. Identification of signal peptide domain SOST mutations in autosomal dominant craniodiaphyseal dysplasia. Hum Genet 129, 497–502 (2011). https://doi.org/10.1007/s00439-011-0947-3

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  • DOI: https://doi.org/10.1007/s00439-011-0947-3

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