2. Academic Validation
  3. MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta

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

  • Nat Commun. 2016 Jul 6;7:11920. doi: 10.1038/ncomms11920.
Uschi Lindert 1,  Wayne A Cabral 2,  Surasawadee Ausavarat 3 4,  Siraprapa Tongkobpetch 3 4,  Katja Ludin 5,  Aileen M Barnes 2,  Patra Yeetong 3 4,  Maryann Weis 6,  Birgit Krabichler 7,  Chalurmpon Srichomthong 3 4,  Elena N Makareeva 8,  Andreas R Janecke 7 9,  Sergey Leikin 8,  Benno Röthlisberger 5,  Marianne Rohrbach 1,  Ingo Kennerknecht 10,  David R Eyre 6,  Kanya Suphapeetiporn 3 4,  Cecilia Giunta 1,  Joan C Marini 2,  Vorasuk Shotelersuk 3 4
Affiliations

Affiliations

  • 1 Division of Metabolism, Connective Tissue Unit and Children's Research Center, University Children's Hospital Zurich, Zurich 8032, Switzerland.
  • 2 Section on Heritable Disorders of Bone and Extracellular Matrix, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • 3 Center of Excellence for Medical Genetics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand.
  • 4 Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok 10330, Thailand.
  • 5 Center for Laboratory Medicine, Department of Medical Genetics, Kantonsspital Aarau, Aarau 5001, Switzerland.
  • 6 Department of Orthopedics and Sports Medicine, University of Washington, Seattle, Washington 98195, USA.
  • 7 Division of Human Genetics, Medical University of Innsbruck, Innsbruck 6020, Austria.
  • 8 Section on Physical Biochemistry, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
  • 9 Department of Pediatrics I, Medical University of Innsbruck, Innsbruck 6020, Austria.
  • 10 Institute of Human Genetics, Westfälische Wilhelms University, Münster 48149, Germany.
PMID: 27380894 DOI: 10.1038/ncomms11920
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.

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