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Title
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Further insights into the pathogenetic mechanisms of melorheostosis and Paget’s disease of bone
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Author
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Abstract
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| Dysregulation of bone remodeling can lead to a large number of skeletal disorders. Elucidating the molecular background of such pathologies has the potential of improving diagnosis and can be of great value in the identification of novel targets for the development of novel therapies. The general aim of this thesis was therefore to investigate the contribution of genetic factors in the pathogenesis of two bone disorders, melorheostosis and Paget’s disease of bone (PDB). In a first part, we performed a mutation analysis in a small cohort of melorheostosis cases. This is a very rare condition characterized by asymmetric increased density of the cortical bone and alteration in surrounding soft tissues. This analysis confirmed the importance of somatic pathogenic variation in the negative regulatory region of MAP2K1 and showed the presence of a novel melorheostosis-associated somatic p.Cys121Ser variant in the catalytic core. Gene-set enrichment of transcriptomic data indicates that this variant leads to hyperactivation of proliferative pERK signaling. The second part of this thesis was focused on PDB. Follow-up of families with a history of PDB further supports the importance of genetic variation in SQSTM1. Based on the molecular background of a number of PDB-related phenotypes, targeted sequencing was performed for a panel of 52 candidate genes. This indicated a significant association for variation in the RIN3 gene with the phenotype, with the rs117068593 variant conferring a protective effect that modifies the age of onset in patients. A panel-wide gene burden analysis highlighted association for a number of genes (TNFRSF11A, NUP205, VCP and NFKBIA) with PDB pathogenesis and suggested an enrichment of rare genetic variation in several other genes (NR4A1, NUP205 and PRKCI). Finally, the use of next-generation sequencing technologies is rapidly expanding the number of candidate genes that requires further functional evaluation. Therefore, we generated a loss-of-function model of the ubiquitin-associated domain in the sqstm1 gene of zebrafish. Preliminary results support the presence of a skeletal phenotype in our model. Further studies will be needed to elucidate whether this reflects an osteoclast-driven Pagetic phenotype. Together, our results provide further insights into the regulation of bone remodeling and explore a novel platform to study the pathogenesis of skeletal disease in vivo. |
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Language
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English
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Publication
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Antwerpen
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Universiteit Antwerpen, Faculteit Farmaceutische, Biomedische en Diergeneeskundige Wetenschappen, Departement Biomedische Wetenschappen
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2021
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Volume/pages
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216 p.
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Note
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Van Hul, Wim [Supervisor]
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Mortier, Geert [Supervisor]
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Full text (publisher's version - intranet only)
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