MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta
Uschi Lindert,Wayne A. Cabral,Surasawadee Ausavarat,Surasawadee Ausavarat,Surasawadee Ausavarat,Siraprapa Tongkobpetch,Siraprapa Tongkobpetch,Katja Ludin,Aileen M. Barnes,Patra Yeetong,Patra Yeetong,MaryAnn Weis,Birgit Krabichler,Chalurmpon Srichomthong,Chalurmpon Srichomthong,Elena Makareeva,Andreas R. Janecke,Sergey Leikin,Benno Röthlisberger,Marianne Rohrbach,Ingo Kennerknecht,David R. Eyre,Kanya Suphapeetiporn,Kanya Suphapeetiporn,Cecilia Giunta,Joan C. Marini,Vorasuk Shotelersuk,Vorasuk Shotelersuk +27 more
Reads0
Chats0
TLDR
An X-linked recessive form of OI caused by defects in MBTPS2, which encodes site-2 metalloprotease (S2P) is identified, providing evidence that RIP plays a fundamental role in normal bone development.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.read more
Citations
More filters
Journal ArticleDOI
Bioinspired mineralized collagen scaffolds for bone tissue engineering.
TL;DR: The state of the art of MCSs as tissue-engineered scaffolds for acceleration of bone repair is summarized, including their fabrication methods, critical factors for osteogenesis regulation, current opportunities and challenges in the future.
Journal ArticleDOI
Osteogenesis imperfecta: an update on clinical features and therapies
TL;DR: Clinically, OI is heterogeneous in features and variable in severity, and new strategies are being explored, such as sclerostin inhibitory antibodies and TGF beta inhibition, to address not only the low bone mineral density but also the inherent bone fragility.
Journal ArticleDOI
Genetic Causes and Mechanisms of Osteogenesis Imperfecta
TL;DR: The known genetic causes of OI, animal models that recapitulate the human disease and mechanisms that underlie disease pathogenesis are summarized and the effects of disrupted collagen networks on extracellular matrix signaling and its impact on disease progression are discussed.
Journal ArticleDOI
Osteogenesis imperfecta: new genes reveal novel mechanisms in bone dysplasia.
TL;DR: The literature is summarized that has contributed to the current understanding of the pathogenesis of OI, a skeletal dysplasia characterized by fragile bones and short stature which is now understood as a collagen-related disorder.
Journal ArticleDOI
Osteogenesis imperfecta and therapeutics.
TL;DR: This short review will describe the clinical features and the molecular genetics of the disease, but then focus on how OI dysregulates all aspects of extracellular matrix biology.
References
More filters
Journal ArticleDOI
ER Stress Induces Cleavage of Membrane-Bound ATF6 by the Same Proteases that Process SREBPs
Jin Ye,Robert B. Rawson,Ryutaro Komuro,Xi Chen,Utpal P. Davé,Ron Prywes,Michael S. Brown,Joseph L. Goldstein +7 more
TL;DR: It is shown that S1P and S2P are required for the ER stress response as well as for lipid synthesis, and ATF6 processing did not require SCAP, which is essential for SREBP processing.
Journal ArticleDOI
SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis
TL;DR: Sterol-regulated proteolysis of a membrane-bound transcription factor provides a novel mechanism by which transcription can be regulated by membrane lipids.
Journal ArticleDOI
Human bone cells in vitro.
TL;DR: Human bone cell cultures established by maintaining collagenase-treated, bone fragments in low Ca++ medium exhibited a high level of alkaline phosphatase activity and produced a significant increase in intracellular cAMP when exposed to the 1–34 fragment of human parathyroid hormone.
Journal ArticleDOI
Homozygosity for a Missense Mutation in SERPINH1, which Encodes the Collagen Chaperone Protein HSP47, Results in Severe Recessive Osteogenesis Imperfecta
Helena E. Christiansen,Ulrike Schwarze,Shawna M. Pyott,Abdulrahman Alswaid,Mohammed Al Balwi,Shatha Alrasheed,Melanie Pepin,MaryAnn Weis,David R. Eyre,Peter H. Byers +9 more
TL;DR: Findings suggest that HSP47 monitors the integrity of the triple helix of type I procollagen at the ER/cis-Golgi boundary and, when absent, the rate of transit from the ER to the Golgi is increased and helical structure is compromised.
Journal ArticleDOI
Signalling mediated by the endoplasmic reticulum stress transducer OASIS is involved in bone formation.
Tomohiko Murakami,Atsushi Saito,Shin-ichiro Hino,Shinichi Kondo,Soshi Kanemoto,Kazuyasu Chihara,Hiroshi Sekiya,Kenji Tsumagari,Kimiko Ochiai,Kazuya Yoshinaga,Masahiro Saitoh,Riko Nishimura,Toshiyuki Yoneda,Ikuyo Kou,Tatsuya Furuichi,Shiro Ikegawa,Masahito Ikawa,Masaru Okabe,Akio Wanaka,Kazunori Imaizumi +19 more
TL;DR: The studies show that OASIS is critical for bone formation through the transcription of Col1a1 and the secretion of bone matrix proteins, and they reveal a new mechanism by which ER stress-induced signalling mediates bone formation.
Related Papers (5)
Exome Sequencing Identifies Truncating Mutations in Human SERPINF1 in Autosomal-Recessive Osteogenesis Imperfecta
CRTAP is required for prolyl 3- hydroxylation and mutations cause recessive osteogenesis imperfecta.
Roy Morello,Terry Bertin,Yuqing Chen,Yuqing Chen,John Hicks,Laura Tonachini,Massimiliano Monticone,Patrizio Castagnola,Frank Rauch,Frank Rauch,Francis H. Glorieux,Francis H. Glorieux,Janice A. Vranka,Janice A. Vranka,Hans Peter Bächinger,Hans Peter Bächinger,James M. Pace,Ulrike Schwarze,Peter H. Byers,MaryAnn Weis,Russell J. Fernandes,David R. Eyre,Zhenqiang Yao,Brendan F. Boyce,Brendan Lee,Brendan Lee,Brendan Lee +26 more
Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans
Joan C. Marini,Antonella Forlino,Antonella Forlino,Wayne A. Cabral,Aileen M. Barnes,James D. San Antonio,Sarah A. Milgrom,James C. Hyland,Jarmo Körkkö,Darwin J. Prockop,Anne De Paepe,Paul Coucke,Sofie Symoens,Francis H. Glorieux,Peter J. Roughley,Alan M. Lund,Kaija Kuurila-Svahn,Heini Hartikka,Daniel H. Cohn,Deborah Krakow,Monica Mottes,Ulrike Schwarze,Diana Chen,Kathleen Yang,Christine D Kuslich,James Troendle,Raymond Dalgleish,Peter H. Byers +27 more