Bone Abstracts (2016) 5 LB9 | DOI: 10.1530/boneabs.5.LB9

First X-linked form of osteogenesis imperfecta, caused by mutations in MBTPS2, demonstrates a fundamental role for regulated intramembrane proteolysis in normal bone formation

Uschi Lindert1, Wayne Cabral2, Surasawadee Ausavarat3,4, Siraprapa Tongkobpetch3,4, Katja Ludin5, Aileen Barnes2, Patra Yeetong3,4, Maryann Weis6, Birgit Krabichler7, Elena Makareeva8, Andreas Janecke7,9, Sergey Leikin8, Benno Röthlisberger5, Marianne Rohrback1, Ingo Kennerknecht10, David Eyre6, Kanya Suphapeetiporn3,4, Cecilia Giunta1, Joan Marini2 & Vorasuk Shotelersuk3,4


1Division of Metabolism, Connective Tissue Unit and Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland; 2Bone and Extracellular Matrix Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA; 3Center of Excellence for Medical Genetics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; 4Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, the Thai Red Cross Society, Bangkok, Thailand; 5Center for Laboratory Medicine, Department of Medical Genetics, Kantonsspital Aarau, Aarau, Switzerland; 6Department of Orthopedics and Sports Medicine, University of Washington, Seattle, WA, USA; 7Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria; 8Section on Physical Biochemistry, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA; 9Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria; 10Institute of Human Genetics, Westfälische Wilhelms University, Münster, Germany.


Osteogenesis imperfecta (OI) is a heritable bone dysplasia with collagen-related defects. Dominantly inherited OI is caused by structural defects in type I collagen or IFITM5, while recessive forms are caused by deficiency of proteins that interact with collagen for modification, folding or cross-linking. We have identified the first X-linked form of OI, caused by a defect in regulated intramembrane proteolysis (RIP). One type of RIP involves sequential cleavage of regulatory proteins, transported from the ER in times of stress or decreased sterol metabolites, by site-1 (S1P) and site-2 (S2P) proteases, releasing N-terminal fragments that activate gene transcription.

In two pedigrees with moderately severe OI, linkage analysis and next generation sequencing identified novel mutations in MBTPS2 (S2P), p.N459S and p.L505F, respectively, located in or near the motif required for metal ion coordination. Neither MBTPS2 transcripts nor protein stability were decreased. Mutant cells and reporter constructs demonstrated impaired cleavage or activation of RIP substrates OASIS, ATF6 and SREBP. Fibroblasts from X-OI probands have significantly reduced type I collagen secretion, consistent with impaired OASIS signaling. Furthermore, extracellular matrix deposited by cultured proband cells has a decreased proportion of collagen with mature crosslinks, suggesting that impaired collagen crosslinking might undermine bone strength in X-OI. A proband bone sample, which became available after the regular abstract submission deadline, contained type I collagen with less than half the normal level of hydroxylation of Lysine 87 (K87), the residue crucial for intermolecular crosslinking. This finding is consistent with decreased Lysyl Hydroxylase 1 levels in proband osteoblast lysates and increased proband urinary LP/HP crosslink ratios. Proband cultured osteoblasts have broadly defective differentiation, with impaired expression of transcripts related to osteoblast maturation and RIP pathways, such as ALPL, CREB3L1 (OASIS), and SMAD4. These studies demonstrate that RIP pathways play a fundamental role in bone development, in addition to their role in cholesterol metabolism.

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