Functional Analyses of Four CYP1A1 Missense Mutations Present in Patients with Atypical Femoral Fractures |
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Authors: | Nerea Ugartondo Núria Martínez-Gil Mnica Esteve Natlia Garcia-Giralt Neus Roca-Ayats Diana Ovejero Xavier Nogus Adolfo Díez-Prez Raquel Rabionet Daniel Grinberg Susanna Balcells |
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Affiliation: | 1.Department of Genetics, Microbiology and Statistics, Faculty of Biology, Universitat de Barcelona, CIBERER, IBUB, IRSJD, 08028 Barcelona, Spain; (N.U.); (N.M.-G.); (M.E.); (N.R.-A.); (R.R.);2.Musculoskeletal Research Group, IMIM (Hospital del Mar Medical Research Institute), Centro de Investigación Biomédica en Red en Fragilidad y Envejecimiento Saludable (CIBERFES), ISCIII, 08003 Barcelona, Spain; (N.G.-G.); (D.O.); (X.N.); (A.D.-P.) |
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Abstract: | Osteoporosis is the most common metabolic bone disorder and nitrogen-containing bisphosphonates (BP) are a first line treatment for it. Yet, atypical femoral fractures (AFF), a rare adverse effect, may appear after prolonged BP administration. Given the low incidence of AFF, an underlying genetic cause that increases the susceptibility to these fractures is suspected. Previous studies uncovered rare CYP1A1 mutations in osteoporosis patients who suffered AFF after long-term BP treatment. CYP1A1 is involved in drug metabolism and steroid catabolism, making it an interesting candidate. However, a functional validation for the AFF-associated CYP1A1 mutations was lacking. Here we tested the enzymatic activity of four such CYP1A1 variants, by transfecting them into Saos-2 cells. We also tested the effect of commonly used BPs on the enzymatic activity of the CYP1A1 forms. We demonstrated that the p.Arg98Trp and p.Arg136His CYP1A1 variants have a significant negative effect on enzymatic activity. Moreover, all the BP treatments decreased CYP1A1 activity, although no specific interaction with CYP1A1 variants was found. Our results provide functional support to the hypothesis that an additive effect between CYP1A1 heterozygous mutations p.Arg98Trp and p.Arg136His, other rare mutations and long-term BP exposure might generate susceptibility to AFF. |
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Keywords: | CYP1A1 osteoporosis atypical femoral fractures bisphosphonates |
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