Mutation of PFN1 Gene in an Early Onset, Polyostotic Paget-like Disease.

Autor:	Merlotti D; Department of Medicine, Surgery and Neurosciences, University of Siena, Italy., Materozzi M; Department of Medicine, Surgery and Neurosciences, University of Siena, Italy.; Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy., Bianciardi S; Department of Medicine, Surgery and Neurosciences, University of Siena, Italy., Guarnieri V; Medical Genetics Service, IRCCS 'Casa Sollievo della Sofferenza' Hospital, San Giovanni Rotondo (FG), Italy., Rendina D; Department of Clinical and Surgical Sciences, Federico II University Medical School, Naples, Italy., Volterrani L; Department of Medicine, Surgery and Neurosciences, University of Siena, Italy., Bellan C; Department of Medical Biotechnologies, University of Siena, Italy., Mingiano C; Department of Medicine, Surgery and Neurosciences, University of Siena, Italy., Picchioni T; Department of Medicine, Surgery and Neurosciences, University of Siena, Italy., Frosali A; Department of Medicine, Surgery and Neurosciences, University of Siena, Italy., Orfanelli U; Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy., Cenci S; Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy., Gennari L; Department of Medicine, Surgery and Neurosciences, University of Siena, Italy.
Jazyk:	angličtina
Zdroj:	The Journal of clinical endocrinology and metabolism [J Clin Endocrinol Metab] 2020 Aug 01; Vol. 105 (8).
DOI:	10.1210/clinem/dgaa252
Abstrakt:	Context: Paget disease of bone (PDB) is a metabolic bone disease whose genetic cause remains unknown in up to 50% of familial patients. Objective: Our aim was to investigate the underlying genetic defect in a large pedigree with a severe, early onset, autosomal dominant form of PDB across 3 generations. Methods: Whole exome sequencing was performed in affected and unaffected family members, and then mutation screening was replicated in a sample of PDB patients with early-onset, polyostotic PDB. Results: We identified a frameshift D107Rfs*3 mutation in PFN1 (encoding for profilin 1, a highly conserved regulator of actin-polymerization and cell motility) causing the truncation of the C-terminal part of the protein. The mutation was also detected in a 17-year-old asymptomatic family member who upon biochemical and radiological analyses was indeed found to be affected. Sequencing of the entire PFN1 coding region in unrelated PDB patients identified the same mutation in 1 patient. All mutation carriers had a reduced response to bisphosphonates, requiring multiple zoledronate infusions to control bone pain and achieve biochemical remission over a long term. In vitro osteoclastogenesis in peripheral blood mononuclear cells (PBMCs) from mutation carriers showed a higher number of osteoclasts with PDB-like features. A similar phenotype was observed upon PFN1 silencing in murine bone marrow-derived monocytes, suggesting that the frameshift PFN1 mutation confers a loss of function in profilin 1 activity that induces PDB-like features in the osteoclasts, likely due to enhanced cell motility and actin ring formation. Conclusions: Our findings indicate that PFN1 mutation causes an early onset, polyostotic PDB-like disorder. (© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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