Abstract
Rare bone disorders are a heterogeneous group of diseases, initially associated with mutations in type I procollagen (PC) genes. Recent developments from dissection at the molecular and cellular level have expanded the list of disease-causing proteins, revealing that disruption of the machinery that handles protein secretion can lead to failure in PC secretion and in several cases result in skeletal dysplasia. In parallel, cell-based in vitro studies of PC trafficking pathways offer clues to the identification of new disease candidate genes. Together, this raises the prospect of heritable bone disorders as a paradigm for biosynthetic protein traffic-related diseases, and an avenue through which therapeutic strategies can be explored.
Here, we focus on human syndromes linked to defects in type I PC secretion with respect to the landscape of biosynthetic and protein transport steps within the early secretory pathway. We provide a perspective on possible therapeutic interventions for associated heritable craniofacial and skeletal disorders, considering different orders of complexity, from the cellular level by manipulation of proteostasis pathways to higher levels involving cell-based therapies for bone repair and regeneration.
Meritxell B. Cutrona and Niamh E. Morgan contributed equally to this work.
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Acknowledgements
The JCS lab acknowledges support from Science Foundation Ireland (SFI), specifically through an SFI Infrastructures award (16/RI/1375). This publication has emanated from research supported in part by a research grant from SFI and is co-funded under the European Regional Development Fund under Grant Number 13/RC/2073. NEM is supported by an Irish Research Council (IRC) postgraduate studentship.
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Cutrona, M.B., Morgan, N.E., Simpson, J.C. (2017). Heritable Skeletal Disorders Arising from Defects in Processing and Transport of Type I Procollagen from the ER: Perspectives on Possible Therapeutic Approaches. In: Ulloa-Aguirre, A., Tao, YX. (eds) Targeting Trafficking in Drug Development. Handbook of Experimental Pharmacology, vol 245. Springer, Cham. https://doi.org/10.1007/164_2017_67
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