Abstract
Heterotopic ossification is a disorder caused by abnormal mineralization of soft tissues in which signaling pathways such as BMP, TGFβ and WNT are known key players in driving ectopic bone formation. Identifying novel genes and pathways related to the mineralization process are important steps for future gene therapy in bone disorders. In this study, we detect an inter-chromosomal insertional duplication in a female proband disrupting a topologically associating domain and causing an ultra-rare progressive form of heterotopic ossification. This structural variant lead to enhancer hijacking and misexpression of ARHGAP36 in fibroblasts, validated here by orthogonal in vitro studies. In addition, ARHGAP36 overexpression inhibits TGFβ, and activates hedgehog signaling and genes/proteins related to extracellular matrix production. Our work on the genetic cause of this heterotopic ossification case has revealed that ARHGAP36 plays a role in bone formation and metabolism, outlining first details of this gene contributing to bone-formation and -disease.
| Original language | English |
|---|---|
| Article number | 2034 |
| Journal | Nature Communications |
| Volume | 14 |
| Issue number | 1 |
| Pages (from-to) | 2034 |
| ISSN | 1751-8628 |
| DOIs | |
| Publication status | Published - 11.04.2023 |
Funding
We would like to thank the family for their contribution to this project, remembering the love and joy that have been donated to the proband. We would like to thank Oliver Rocks, Institute of Biochemistry—Charité, Germany, for the courtesy of the ARHGAP36 plasmid and Walter Sebald, University of Würzburg, Germany, for the rhBMP2. The authors would also like to thank the BCRT Cell Harvesting Core Unit (BCRT-CH) of the Berlin Institute of Health, Charité—Universitätsmedizin Berlin, for their excellent technical assistance and support. This study was supported by the German Federal Ministry of Education and Research (BMBF, 031L0234B), the European Union’s Horizon 2020 research and innovation program (Grant No. 779293), and the German Research Foundation (DFG) through funding of the Research Group 2165 (GE2512/2-2), (SFB1444) to P.K. and the Collaborative Research Center 1444. This study was also supported by the Baylor-Hopkins Center for Mendelian Genomics through National Human Genome Research Institute grant 5U54HG006542 (genome sequencing), Ministero dell’Istruzione, dell’Università e della Ricerca—MIUR “Dipartimenti di Eccellenza 2018–2022” to Department of Medical Sciences, University of Torino (Project no. D15D18000410001), and Italian Ministry of Health (5 × 1000), Fondazione Bambino Gesù (Vite Coraggiose) to M.T. We would like to thank the family for their contribution to this project, remembering the love and joy that have been donated to the proband. We would like to thank Oliver Rocks, Institute of Biochemistry—Charité, Germany, for the courtesy of the ARHGAP36 plasmid and Walter Sebald, University of Würzburg, Germany, for the rhBMP2. The authors would also like to thank the BCRT Cell Harvesting Core Unit (BCRT-CH) of the Berlin Institute of Health, Charité—Universitätsmedizin Berlin, for their excellent technical assistance and support. This study was supported by the German Federal Ministry of Education and Research (BMBF, 031L0234B), the European Union’s Horizon 2020 research and innovation program (Grant No. 779293), and the German Research Foundation (DFG) through funding of the Research Group 2165 (GE2512/2-2), (SFB1444) to P.K. and the Collaborative Research Center 1444. This study was also supported by the Baylor-Hopkins Center for Mendelian Genomics through National Human Genome Research Institute grant 5U54HG006542 (genome sequencing), Ministero dell’Istruzione, dell’Università e della Ricerca—MIUR “Dipartimenti di Eccellenza 2018–2022” to Department of Medical Sciences, University of Torino (Project no. D15D18000410001), and Italian Ministry of Health (5 × 1000), Fondazione Bambino Gesù (Vite Coraggiose) to M.T.
Research Areas and Centers
- Research Area: Medical Genetics
DFG Research Classification Scheme
- 2.22-03 Human Genetics
