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Genetic Variation in RIN3 in the Belgian Population Supports Its Involvement in the Pathogenesis of Paget’s Disease of Bone and Modifies the Age of Onset

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Abstract

Paget’s disease of bone (PDB) is a common, late-onset bone disorder characterized by focal increase of bone turnover. Mutations in the SQSTM1 gene are found in up to 40% of patients and recent GWAS have led to novel associations with several loci. RIN3, the candidate gene located at the associated 14q32 locus, has recently been studied in a British cohort to elucidate its contribution to the pathogenesis. In this study, we performed a genetic screening of RIN3 in an unrelated cohort to validate these findings and to further explore genetic variation in this gene in the context of PDB. In our screening, we examined the 5′ untranslated region (UTR), the exonic regions and the intron–exon boundaries of the gene in a control cohort and a patient cohort. Our findings show clustering of variation similar to the British cohort and support a protective role for common genetic variation (rs117068593, p.R279C) in the proline-rich region and a functionally relevant role for rare genetic variation in the domains that mediate binding and activation of its interaction partner, Rab5. Additive regression models, fitted for the common variants, validated the association of the rs117068593 variant with the disease (OR+/+ 0.315; OR+/− 0.562). In addition, our analyses revealed a potentially modifying effect of this variant on the age of onset of the disease. In conclusion, our findings support the involvement of genetic variation in RIN3 in PDB and suggest a role for RIN3 as a potential modifier of the age of onset of the disease.

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Acknowledgements

The authors would like to thank Alex Hoischen (Radboudumc Nijmegen) for his help in the probe design used in our targeted sequencing approach.

Funding

This work was supported by grants of the ‘Fonds voor Wetenschappelijk Onderzoek Vlaanderen’ (FWO Grant G019712N and G031915N) and the European Community’s Seventh Framework Programme (FP7/2007–2013) under Grant Agreement No. 602300 (SYBIL). RDR holds a doctoral grant with the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (1S07717N). EB and GV hold postdoctoral Grants (12A3814N and 12D1717N) with the Fonds voor Wetenschappelijk Onderzoek Vlaanderen.

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  1. Center of Medical Genetics, University of Antwerp & Antwerp University Hospital, Prins Boudewijnlaan 43, Edegem, 2650, Antwerp, Belgium

    Raphaël De Ridder, Eveline Boudin, Geert Vandeweyer, Erik Fransen, Geert Mortier & Wim Van Hul

  2. Department of Rheumatology, Saint-Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium

    Jean-Pierre Devogelaer

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De Ridder, R., Boudin, E., Vandeweyer, G. et al. Genetic Variation in RIN3 in the Belgian Population Supports Its Involvement in the Pathogenesis of Paget’s Disease of Bone and Modifies the Age of Onset. Calcif Tissue Int 104, 613–621 (2019). https://doi.org/10.1007/s00223-019-00530-3

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