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

Uschi Lindert, Wayne A. Cabral, Surasawadee Ausavarat, Siraprapa Tongkobpetch, Katja Ludin, Aileen M. Barnes, Patra Yeetong, Maryann Weis, Birgit Krabichler, Chalurmpon Srichomthong, Elena N. Makareeva, Andreas R. Janecke, Sergey Leikin, Benno Röthlisberger, Marianne Rohrbach, Ingo Kennerknecht, David R. Eyre, Kanya Suphapeetiporn, Cecilia Giunta, Joan C. Marini () and Vorasuk Shotelersuk
Additional contact information
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
Siraprapa Tongkobpetch: Center of Excellence for Medical Genetics, Faculty of Medicine, Chulalongkorn University
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
Maryann Weis: University of Washington
Birgit Krabichler: Medical University of Innsbruck
Chalurmpon Srichomthong: Center of Excellence for Medical Genetics, Faculty of Medicine, Chulalongkorn University
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
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
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

Nature Communications, 2016, vol. 7, issue 1, 1-12

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11920

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