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

Melissa Formosa, Dylan J M Bergen, Celia L Gregson, Antonio Maurizi, Anders Kampe, Natalia Garcia-Giralt, Wei Zhou, Daniel Grindberg, Diana Ovejero Crespo, M. Carola Zilikens, Graham Williams, J. H. Duncan Bassett, Maria Luisa Brandi, Luca Sangiorgi, Wolfgang Hogler, Wim van Hul, Outi Mäkitie*

*Corresponding author for this work

Research output: Contribution to journalReview article (Academic Journal)peer-review

4 Downloads (Pure)

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.
Original languageEnglish
Article number709711
JournalFrontiers in Endocrinology
Volume12
DOIs
Publication statusPublished - 13 Aug 2021

Bibliographical note

Funding Information:
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).

Publisher Copyright:
© Copyright © 2021 Formosa, Bergen, Gregson, Maurizi, Kämpe, Garcia-Giralt, Zhou, Grinberg, Ovejero Crespo, Zillikens, Williams, Bassett, Brandi, Sangiorgi, Balcells, Högler, Van Hul and Mäkitie.

Keywords

  • bone mass
  • skeletal dysplasia
  • GEMSTONE
  • monogenic bone disorders
  • drug discovery
  • functional validation
  • gene variants

Fingerprint

Dive into the research topics of 'A Roadmap to Gene Discoveries and Novel Therapies in Monogenic Low and High Bone Mass Disorders'. Together they form a unique fingerprint.

Cite this