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MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta

Author

Listed:
  • Uschi Lindert

    (Connective Tissue Unit and Children’s Research Center, University Children’s Hospital Zurich)

  • Wayne A. Cabral

    (Section on Heritable Disorders of Bone and Extracellular Matrix, National Institute of Child Health and Human Development, National Institutes of Health)

  • Surasawadee Ausavarat

    (Center of Excellence for Medical Genetics, Faculty of Medicine, Chulalongkorn University
    Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society
    Present address: Division of Nuclear Medicine, Department of Radiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand)

  • Siraprapa Tongkobpetch

    (Center of Excellence for Medical Genetics, Faculty of Medicine, Chulalongkorn University
    Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society)

  • Katja Ludin

    (Center for Laboratory Medicine)

  • Aileen M. Barnes

    (Section on Heritable Disorders of Bone and Extracellular Matrix, National Institute of Child Health and Human Development, National Institutes of Health)

  • Patra Yeetong

    (Center of Excellence for Medical Genetics, Faculty of Medicine, Chulalongkorn University
    Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society
    Present address: Division of Human Genetics, Department of Botany, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand)

  • Maryann Weis

    (University of Washington)

  • Birgit Krabichler

    (Medical University of Innsbruck)

  • Chalurmpon Srichomthong

    (Center of Excellence for Medical Genetics, Faculty of Medicine, Chulalongkorn University
    Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society)

  • Elena N. Makareeva

    (Section on Physical Biochemistry, National Institute of Child Health and Human Development, National Institutes of Health)

  • Andreas R. Janecke

    (Medical University of Innsbruck
    Medical University of Innsbruck)

  • Sergey Leikin

    (Section on Physical Biochemistry, National Institute of Child Health and Human Development, National Institutes of Health)

  • Benno Röthlisberger

    (Center for Laboratory Medicine)

  • Marianne Rohrbach

    (Connective Tissue Unit and Children’s Research Center, University Children’s Hospital Zurich)

  • Ingo Kennerknecht

    (Institute of Human Genetics, Westfälische Wilhelms University)

  • David R. Eyre

    (University of Washington)

  • Kanya Suphapeetiporn

    (Center of Excellence for Medical Genetics, Faculty of Medicine, Chulalongkorn University
    Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society)

  • Cecilia Giunta

    (Connective Tissue Unit and Children’s Research Center, University Children’s Hospital Zurich)

  • Joan C. Marini

    (Section on Heritable Disorders of Bone and Extracellular Matrix, National Institute of Child Health and Human Development, National Institutes of Health)

  • Vorasuk Shotelersuk

    (Center of Excellence for Medical Genetics, Faculty of Medicine, Chulalongkorn University
    Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society)

Abstract

Osteogenesis imperfecta (OI) is a collagen-related bone dysplasia. We identified an X-linked recessive form of OI caused by defects in MBTPS2, which encodes site-2 metalloprotease (S2P). MBTPS2 missense mutations in two independent kindreds with moderate/severe OI cause substitutions at highly conserved S2P residues. Mutant S2P has normal stability, but impaired functioning in regulated intramembrane proteolysis (RIP) of OASIS, ATF6 and SREBP transcription factors, consistent with decreased proband secretion of type I collagen. Further, hydroxylation of the collagen lysine residue (K87) critical for crosslinking is reduced in proband bone tissue, consistent with decreased lysyl hydroxylase 1 in proband osteoblasts. Reduced collagen crosslinks presumptively undermine bone strength. Also, proband osteoblasts have broadly defective differentiation. These mutations provide evidence that RIP plays a fundamental role in normal bone development.

Suggested Citation

  • Uschi Lindert & Wayne A. Cabral & Surasawadee Ausavarat & Siraprapa Tongkobpetch & Katja Ludin & Aileen M. Barnes & Patra Yeetong & Maryann Weis & Birgit Krabichler & Chalurmpon Srichomthong & Elena N, 2016. "MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta," Nature Communications, Nature, vol. 7(1), pages 1-12, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11920
    DOI: 10.1038/ncomms11920
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