Genetic disorders of the skeleton encompass a diverse group of bone diseases differing in clinical characteristics, severity, incidence and molecular etiology. Of particular interest are the monogenic rare bone mass disorders, with the underlying genetic defect contributing to either low or high bone mass phenotype. Extensive, deep phenotyping coupled with high-throughput, cost-effective genotyping is crucial in the characterization and diagnosis of affected individuals. Massive parallel sequencing efforts have been instrumental in the discovery of novel causal genes that merit functional validation using in vitro and ex vivo cell-based techniques, and in vivo models, mainly mice and zebrafish. These translational models also serve as an excellent platform for therapeutic discovery, bridging the gap between basic science research and the clinic. Altogether, genetic studies of monogenic rare bone mass disorders have broadened our knowledge on molecular signaling pathways coordinating bone development and metabolism, disease inheritance patterns, development of new and improved bone biomarkers, and identification of novel drug targets. In this comprehensive review we describe approaches to further enhance the innovative processes taking discoveries from clinic to bench, and then back to clinic in rare bone mass disorders. We highlight the importance of cross laboratory collaboration to perform functional validation in multiple model systems after identification of a novel disease gene. We describe the monogenic forms of rare low and high rare bone mass disorders known to date, provide a roadmap to unravel the genetic determinants of monogenic rare bone mass disorders using proper phenotyping and genotyping methods, and describe different genetic validation approaches paving the way for future treatments.
Funding was obtained from the GEMSTONE COST Action (CA18139). MMF has received research funds from The University of Malta Research, Innovation and Development Trust and The Malta Community Chest Fund, and the Research Excellence Programme (REP-2020-011; Project GeOM financed by the Malta Council for Science & Technology, for and on behalf of the Foundation for Science and Technology, through the Research Excellence Programme). DB is funded by the Foundation Fellowship from Versus Arthritis (Grant no. 22044). NG-G and DC are supported by
This publication is based upon work from COST Action GEMSTONE, supported by COST (European Cooperation in Science and Technology). COST is a funding agency for research and innovation networks. Our Actions help connect research initiatives across Europe and enable scientists to grow their ideas by sharing them with their peers. This boosts their research, career and innovation (www.cost.eu).
© Copyright © 2021 Formosa, Bergen, Gregson, Maurizi, Kämpe, Garcia-Giralt, Zhou, Grinberg, Ovejero Crespo, Zillikens, Williams, Bassett, Brandi, Sangiorgi, Balcells, Högler, Van Hul and Mäkitie.
- bone mass
- skeletal dysplasia
- monogenic bone disorders
- drug discovery
- functional validation
- gene variants