A roadmap to gene discoveries and novel therapies in monogenic low and high bone mass disorders

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• dc.contributor.author Formosa, Melissa M.
• dc.contributor.author Bergen, Dylan J.M.
• dc.contributor.author Gregson, Celia L.
• dc.contributor.author Maurizi, Antonio
• dc.contributor.author Kämpe, Anders
• dc.contributor.author Garcia Giralt, Natàlia
• dc.contributor.author Zhou, Wei
• dc.contributor.author Grinberg, Daniel
• dc.contributor.author Ovejero Crespo, Diana
• dc.contributor.author Zillikens, M. Carola
• dc.contributor.author Williams, Graham R.
• dc.contributor.author Bassett, J.H. Duncan
• dc.contributor.author Brandi, María Luisa
• dc.contributor.author Sangiorgi, Luca
• dc.contributor.author Balcells, Susana
• dc.contributor.author Högler, Wolfgang
• dc.contributor.author Van Hul, Wim
• dc.contributor.author Mäkitie, Outi
• dc.date.accessioned 2022-06-08T07:47:58Z
• dc.date.available 2022-06-08T07:47:58Z
• dc.date.issued 2021
• dc.description.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.
• dc.description.sponsorship 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 CIBERFES (CB16/10/00245 [ISCIII]), FEIOMM2019 and European Regional Development Fund (ERDF). WZ is funded by the Jaap Schouten Foundation (The Netherlands). WVH received a Methusalem-OEC grant for the project “GENOMED” and a Research Fund of the University of Antwerp (FFB190208). MB has received funding from La Fondazione Italiana Ricerca sulle Malattie dell’Osso. The Origins of Bone and Cartilage Disease Programme analysed the skeletal phenotype of knockout mice generated by the International Mouse Phenotyping Consortium (IMPC) and was funded by a Wellcome Trust Strategic Award (101123) to GW and JB. OM is funded by the Sigrid Jusélius Foundation. DG and SB declare that this study received funding from MINECO (SAF2016-75948R and PID2019-107188RB-C21). The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.
• dc.format.mimetype application/pdf
• dc.identifier.citation Formosa MM, Bergen DJM, Gregson CL, Maurizi A, Kämpe A, Garcia-Giralt N, et al. A roadmap to gene discoveries and novel therapies in monogenic low and high bone mass disorders.Front Endocrinol (Lausanne). 2021 Aug 13; 12: 709711. DOI: 10.3389/fendo.2021.709711
• dc.identifier.doi http://dx.doi.org/10.3389/fendo.2021.709711
• dc.identifier.issn 1664-2392
• dc.identifier.uri http://hdl.handle.net/10230/53405
• dc.language.iso eng
• dc.publisher Frontiers
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2016-75948R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-107188RB-C21
• dc.rights copyright © 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). http://creativecommons.org/licenses/by/4.0/. 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.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword GEMSTONE
• dc.subject.keyword Bone mass
• dc.subject.keyword Drug discovery
• dc.subject.keyword Functional validation
• dc.subject.keyword Gene variants
• dc.subject.keyword Monogenic bone disorders
• dc.subject.keyword Skeletal dysplasia
• dc.title A roadmap to gene discoveries and novel therapies in monogenic low and high bone mass disorders
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion