TY - JOUR
T1 - Collagen transport and related pathways in Osteogenesis Imperfecta
AU - Claeys, Lauria
AU - Storoni, Silvia
AU - Eekhoff, Marelise
AU - Elting, Mariet
AU - Wisse, Lisanne
AU - Pals, Gerard
AU - Bravenboer, Nathalie
AU - Maugeri, Alessandra
AU - Micha, Dimitra
N1 - Funding Information: Figure?1 was created with BioRender.com by using adapted images from SERVIER MEDICAL ART provided by Les Laboratoires Servier, which falls under the creative commons? attribution 3.0 unported license. Funding Information: The work of Lauria Claeys, Dimitra Micha and Gerard Pals was funded by the kind donation of Hans Horsting and Mary Horsting-Stuit of the Horstingstuit foundation. Dimitra Micha is also funded by the Amsterdam Movement Sciences Innovation call grant. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/8/1
Y1 - 2021/8/1
N2 - Osteogenesis Imperfecta (OI) comprises a heterogeneous group of patients who share bone fragility and deformities as the main characteristics, albeit with different degrees of severity. Phenotypic variation also exists in other connective tissue aspects of the disease, complicating disease classification and disease course prediction. Although collagen type I defects are long established as the primary cause of the bone pathology, we are still far from comprehending the complete mechanism. In the last years, the advent of next generation sequencing has triggered the discovery of many new genetic causes for OI, helping to draw its molecular landscape. It has become clear that, in addition to collagen type I genes, OI can be caused by multiple proteins connected to different parts of collagen biosynthesis. The production of collagen entails a complex process, starting from the production of the collagen Iα1 and collagen Iα2 chains in the endoplasmic reticulum, during and after which procollagen is subjected to a plethora of posttranslational modifications by chaperones. After reaching the Golgi organelle, procollagen is destined to the extracellular matrix where it forms collagen fibrils. Recently discovered mutations in components of the retrograde transport of chaperones highlight its emerging role as critical contributor of OI development. This review offers an overview of collagen regulation in the context of recent gene discoveries, emphasizing the significance of transport disruptions in the OI mechanism. We aim to motivate exploration of skeletal fragility in OI from the perspective of these pathways to identify regulatory points which can hint to therapeutic targets.
AB - Osteogenesis Imperfecta (OI) comprises a heterogeneous group of patients who share bone fragility and deformities as the main characteristics, albeit with different degrees of severity. Phenotypic variation also exists in other connective tissue aspects of the disease, complicating disease classification and disease course prediction. Although collagen type I defects are long established as the primary cause of the bone pathology, we are still far from comprehending the complete mechanism. In the last years, the advent of next generation sequencing has triggered the discovery of many new genetic causes for OI, helping to draw its molecular landscape. It has become clear that, in addition to collagen type I genes, OI can be caused by multiple proteins connected to different parts of collagen biosynthesis. The production of collagen entails a complex process, starting from the production of the collagen Iα1 and collagen Iα2 chains in the endoplasmic reticulum, during and after which procollagen is subjected to a plethora of posttranslational modifications by chaperones. After reaching the Golgi organelle, procollagen is destined to the extracellular matrix where it forms collagen fibrils. Recently discovered mutations in components of the retrograde transport of chaperones highlight its emerging role as critical contributor of OI development. This review offers an overview of collagen regulation in the context of recent gene discoveries, emphasizing the significance of transport disruptions in the OI mechanism. We aim to motivate exploration of skeletal fragility in OI from the perspective of these pathways to identify regulatory points which can hint to therapeutic targets.
UR - http://www.scopus.com/inward/record.url?scp=85110476598&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s00439-021-02302-2
DO - https://doi.org/10.1007/s00439-021-02302-2
M3 - Review article
C2 - 34169326
SN - 0340-6717
VL - 140
SP - 1121
EP - 1141
JO - Human genetics
JF - Human genetics
IS - 8
ER -