Functional analyses of four CYP1A1 missense mutations present in patients with atypical femoral fractures
Mostra el registre complet Registre parcial de l'ítem
- dc.contributor.author Ugartondo, Nerea
- dc.contributor.author Martínez-Gil, Núria
- dc.contributor.author Esteve, Mònica
- dc.contributor.author Garcia Giralt, Natàlia
- dc.contributor.author Roca Ayats, Neus
- dc.contributor.author Ovejero Crespo, Diana
- dc.contributor.author Nogués Solan, Francesc Xavier
- dc.contributor.author Díez Pérez, Adolfo
- dc.contributor.author Rabionet, Raquel
- dc.contributor.author Grinberg, Daniel
- dc.contributor.author Balcells, Susana
- dc.date.accessioned 2022-03-01T07:05:37Z
- dc.date.available 2022-03-01T07:05:37Z
- dc.date.issued 2021
- dc.description.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.
- dc.description.sponsorship Funding was available from Fundación Española de Investigación Ósea y Metabolismo Mineral (“Beca FEIOMM 2019 de Investigación Básica”) and grant PID2019-107188RB-C21 from the Spanish Ministerio de Ciencia e Innovación. N.M.G. and N.R.A. were recipients of Ph.D. fellowships from AGAUR (Catalan Government) and the Spanish Ministerio de Universidades.
- dc.format.mimetype application/pdf
- dc.identifier.citation Ugartondo N, Martínez-Gil N, Esteve M, Garcia-Giralt N, Roca-Ayats N, Ovejero D, Nogués X, Díez-Pérez A, Rabionet R, Grinberg D, Balcells S. Functional analyses of four CYP1A1 missense mutations present in patients with atypical femoral fractures. Int J Mol Sci. 2021 Jul 9;22(14):7395. DOI: 10.3390/ijms22147395
- dc.identifier.doi http://dx.doi.org/10.3390/ijms22147395
- dc.identifier.issn 1422-0067
- dc.identifier.uri http://hdl.handle.net/10230/52592
- dc.language.iso eng
- dc.publisher MDPI
- dc.relation.ispartof Int J Mol Sci. 2021 Jul 9;22(14):7395
- dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-107188RB-C21
- dc.rights © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/by/4.0/
- dc.subject.keyword CYP1A1
- dc.subject.keyword Atypical femoral fractures
- dc.subject.keyword Bisphosphonates
- dc.subject.keyword Osteoporosis
- dc.title Functional analyses of four CYP1A1 missense mutations present in patients with atypical femoral fractures
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion