A Roadmap to gene discoveries and novel therapies in monogenic low and high bone mass disorders
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
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.
Date Issued
2021-08
Date Acceptance
2021-07-12
Citation
Frontiers in Endocrinology, 2021, 12, pp.1-24
ISSN
1664-2392
Publisher
Frontiers Media
Start Page
1
End Page
24
Journal / Book Title
Frontiers in Endocrinology
Volume
12
Copyright Statement
© 2021 Formosa, Bergen, Gregson, Maurizi, Kämpe, Garcia-Giralt, Zhou, Grinberg, Ovejero Crespo, Zillikens, Williams, Bassett, Brandi, Sangiorgi, Balcells, Högler, Van Hul and Mäkitie. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
License URL
Identifier
https://www.frontiersin.org/articles/10.3389/fendo.2021.709711/full
Subjects
1103 Clinical Sciences
1111 Nutrition and Dietetics
Publication Status
Published
Article Number
709711
Date Publish Online
2021-08-13