A Roadmap to Gene Discoveries and Novel Therapies in Monogenic Low and High Bone Mass Disorders

Formosa M et al. Front. Endocrinol., 13 August 2021

REVIEW article

Front. Endocrinol., 13 August 2021 | https://doi.org/10.3389/fendo.2021.709711

Melissa M. Formosa^1,2, Dylan J. M. Bergen^3,4, Celia L. Gregson⁴, Antonio Maurizi⁵, Anders Kämpe^6,7, Natalia Garcia-Giralt⁸, Wei Zhou⁹, Daniel Grinberg¹⁰, Diana Ovejero Crespo⁸, M. Carola Zillikens⁹, Graham R. Williams¹¹, J. H. Duncan Bassett¹¹, Maria Luisa Brandi¹², Luca Sangiorgi¹³, Susanna Balcells¹⁰, Wolfgang Högler^14,15, Wim Van Hul¹⁶ and Outi Mäkitie^17,18,19* on behalf of GEMSTONE Working Group 3 COST Action

• ¹Department of Applied Biomedical Science, Faculty of Health Sciences, University of Malta, Msida, Malta
• ²Centre for Molecular Medicine and Biobanking, University of Malta, Msida, Malta
• ³School of Physiology, Pharmacology, and Neuroscience, Faculty of Life Sciences, University of Bristol, Bristol, United Kingdom
• ⁴The Musculoskeletal Research Unit, Translational Health Sciences, Bristol Medical School, Faculty of Health Sciences, University of Bristol, Bristol, United Kingdom
• ⁵Department of Applied Clinical Sciences and Biotechnological, University of L’Aquila, L’Aquila, Italy
• ⁶Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
• ⁷Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
• ⁸IMIM (Hospital del Mar Research Institute), Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Barcelona, Spain
• ⁹Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands
• ¹⁰Department of Genetics, Microbiology and Statistics, Faculty of Biology, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Institut de Biomedicina de la Universitat de Barcelona (IBUB), Institut de Recerca Sant Joan de Déu (IRSJD), Barcelona, Spain
• ¹¹Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom
• ¹²Department of Surgery and Translational Medicine (M.L.B.), University of Florence, Florence, Italy
• ¹³Department of Medical Genetics and Skeletal Rare Diseases, IRCCS Rizzoli Orthopaedic Institute, Bologna, Italy
• ¹⁴Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz, Linz, Austria
• ¹⁵Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, United Kingdom
• ¹⁶Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
• ¹⁷Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
• ¹⁸Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland
• ¹⁹Folkhälsan Research Centre, Folkhälsan Institute of Genetics, Helsinki, Finland

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.

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