Functional Characterization of a GGPPS Variant Identified in Atypical Femoral Fracture Patients and Delineation of the Role of GGPPS in Bone-Relevant Cell Types.
Por:
Roca N, Ng PY, Garcia-Giralt N, Falcó-Mascaró M, Cozar M, Abril JF, Quesada Gómez JM, Prieto-Alhambra D, Nogués X, Dunford JE, Russell RG, Baron R, Grinberg-Vaisman DR, Balcells S and Díez-Pérez A
Publicada:
1 dic 2018
Ahead of Print:
24 sep 2018
Resumen:
Atypical femoral fractures (AFFs) are a rare but potentially devastating event, often but not always linked to bisphosphonate (BP) therapy. The pathogenic mechanisms underlying AFFs remain obscure, and there are no tests available that might assist in identifying those at high risk of AFF. We previously used exome sequencing to explore the genetic background of three sisters with AFFs and three additional unrelated AFF cases, all previously treated with BPs. We detected 37 rare mutations (in 34 genes) shared by the three sisters. Notably, we found a p.Asp188Tyr mutation in the enzyme geranylgeranyl pyrophosphate synthase, a component of the mevalonate pathway, which is critical to osteoclast function and is inhibited by N-BPs. In addition, the CYP1A1 gene, responsible for the hydroxylation of 17ß-estradiol, estrone, and vitamin D, was also mutated in all three sisters and one unrelated patient. Here we present a detailed list of the variants found and report functional analyses of the GGPS1 p.Asp188Tyr mutation, which showed a severe reduction in enzyme activity together with oligomerization defects. Unlike BP treatment, this genetic mutation will affect all cells in the carriers. RNAi knockdown of GGPS1 in osteoblasts produced a strong mineralization reduction and a reduced expression of osteocalcin, osterix, and RANKL, whereas in osteoclasts, it led to a lower resorption activity. Taken together, the impact of the mutated GGPPS and the relevance of the downstream effects in bone cells make it a strong candidate for AFF susceptibility. We speculate that other genes such as CYP1A1 might be involved in AFF pathogenesis, which remains to be functionally proved. The identification of the genetic background for AFFs provides new insights for future development of novel risk assessment tools. © 2018 American Society for Bone and Mineral Research.
Filiaciones:
Roca N:
Department of Genetics, Microbiology and Statistics, Facultat de Biologia, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, IBUB, IRSJD, Barcelona, Catalonia, Spain
Ng PY:
Division of Bone and Mineral Research, Department of Oral Medicine, Harvard School of Dental Medicine, and Department of Medicine, Harvard Medical School, Boston, MA, United States
Garcia-Giralt N:
Musculoskeletal Research Group, IMIM (Hospital del Mar Medical Research Institute), Centro de Investigación Biomédica en Red en Fragilidad y Envejecimiento Saludable (CIBERFES), ISCIII, Barcelona, Catalonia, Spain
Falcó-Mascaró M:
Department of Genetics, Microbiology and Statistics, Facultat de Biologia, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, IBUB, IRSJD, Barcelona, Catalonia, Spain
Cozar M:
Department of Genetics, Microbiology and Statistics, Facultat de Biologia, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, IBUB, IRSJD, Barcelona, Catalonia, Spain
Abril JF:
Department of Genetics, Microbiology and Statistics, Facultat de Biologia, Universitat de Barcelona, IBUB
Barcelona, Catalonia, Spain
Quesada Gómez JM:
Mineral Metabolism Unit, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, CIBERFES, ISCII, Córdoba, Spain
Prieto-Alhambra D:
GREMPAL (Grup de Recerca en Malalties Prevalents de l'Aparell Locomotor), Idiap Jordi Gol Primary Care Research Institute, CIBERFES, Autonomous University of Barcelona, Barcelona, Spain
NIHR Musculoskeletal BRU Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
Nogués X:
Musculoskeletal Research Group, IMIM (Hospital del Mar Medical Research Institute), Centro de Investigación Biomédica en Red en Fragilidad y Envejecimiento Saludable (CIBERFES), ISCIII, Barcelona, Catalonia, Spain
Dunford JE:
NIHR Musculoskeletal BRU Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
Russell RG:
NIHR Musculoskeletal BRU Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom
The Mellanby Centre for Bone Research, Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom
Baron R:
Division of Bone and Mineral Research, Department of Oral Medicine, Harvard School of Dental Medicine, and Department of Medicine, Harvard Medical School, Boston, MA, United States
Grinberg-Vaisman DR:
Department of Genetics, Microbiology and Statistics, Facultat de Biologia, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, IBUB, IRSJD, Barcelona, Catalonia, Spain
Balcells S:
Department of Genetics, Microbiology and Statistics, Facultat de Biologia, Universitat de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, IBUB, IRSJD, Barcelona, Catalonia, Spain
Díez-Pérez A:
Musculoskeletal Research Group, IMIM (Hospital del Mar Medical Research Institute), Centro de Investigación Biomédica en Red en Fragilidad y Envejecimiento Saludable (CIBERFES), ISCIII, Barcelona, Catalonia, Spain
Open Access
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