Functional analyses of four CYP1A1 missense mutations present in patients with atypical femoral fractures

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 ca...

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Detalles Bibliográficos
Autores: Ugartondo, Nerea, Martínez-Gil, Núria, Esteve, Mònica, Garcia Giralt, Natàlia, Roca Ayats, Neus, Ovejero Crespo, Diana, Nogués Solán, Xavier, Díez Pérez, Adolfo, Rabionet Janssen, Raquel, Grinberg, Daniel, Balcells, Susana
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Universitat Pompeu Fabra
Repositorio:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/52592
Acceso en línea:http://hdl.handle.net/10230/52592
http://dx.doi.org/10.3390/ijms22147395
Access Level:acceso abierto
Palabra clave:CYP1A1
Atypical femoral fractures
Bisphosphonates
Osteoporosis
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spelling Functional analyses of four CYP1A1 missense mutations present in patients with atypical femoral fracturesUgartondo, NereaMartínez-Gil, NúriaEsteve, MònicaGarcia Giralt, NatàliaRoca Ayats, NeusOvejero Crespo, DianaNogués Solán, XavierDíez Pérez, AdolfoRabionet Janssen, RaquelGrinberg, DanielBalcells, SusanaCYP1A1Atypical femoral fracturesBisphosphonatesOsteoporosisOsteoporosis 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.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.MDPI202220222021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/52592http://dx.doi.org/10.3390/ijms22147395reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésInt J Mol Sci. 2021 Jul 9;22(14):7395info:eu-repo/grantAgreement/ES/2PE/PID2019-107188RB-C21© 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/).http://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/525922026-06-12T07:21:37Z
dc.title.none.fl_str_mv Functional analyses of four CYP1A1 missense mutations present in patients with atypical femoral fractures
title Functional analyses of four CYP1A1 missense mutations present in patients with atypical femoral fractures
spellingShingle Functional analyses of four CYP1A1 missense mutations present in patients with atypical femoral fractures
Ugartondo, Nerea
CYP1A1
Atypical femoral fractures
Bisphosphonates
Osteoporosis
title_short Functional analyses of four CYP1A1 missense mutations present in patients with atypical femoral fractures
title_full Functional analyses of four CYP1A1 missense mutations present in patients with atypical femoral fractures
title_fullStr Functional analyses of four CYP1A1 missense mutations present in patients with atypical femoral fractures
title_full_unstemmed Functional analyses of four CYP1A1 missense mutations present in patients with atypical femoral fractures
title_sort Functional analyses of four CYP1A1 missense mutations present in patients with atypical femoral fractures
dc.creator.none.fl_str_mv Ugartondo, Nerea
Martínez-Gil, Núria
Esteve, Mònica
Garcia Giralt, Natàlia
Roca Ayats, Neus
Ovejero Crespo, Diana
Nogués Solán, Xavier
Díez Pérez, Adolfo
Rabionet Janssen, Raquel
Grinberg, Daniel
Balcells, Susana
author Ugartondo, Nerea
author_facet Ugartondo, Nerea
Martínez-Gil, Núria
Esteve, Mònica
Garcia Giralt, Natàlia
Roca Ayats, Neus
Ovejero Crespo, Diana
Nogués Solán, Xavier
Díez Pérez, Adolfo
Rabionet Janssen, Raquel
Grinberg, Daniel
Balcells, Susana
author_role author
author2 Martínez-Gil, Núria
Esteve, Mònica
Garcia Giralt, Natàlia
Roca Ayats, Neus
Ovejero Crespo, Diana
Nogués Solán, Xavier
Díez Pérez, Adolfo
Rabionet Janssen, Raquel
Grinberg, Daniel
Balcells, Susana
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CYP1A1
Atypical femoral fractures
Bisphosphonates
Osteoporosis
topic CYP1A1
Atypical femoral fractures
Bisphosphonates
Osteoporosis
description 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.
publishDate 2021
dc.date.none.fl_str_mv 2021
2022
2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/52592
http://dx.doi.org/10.3390/ijms22147395
url http://hdl.handle.net/10230/52592
http://dx.doi.org/10.3390/ijms22147395
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Int J Mol Sci. 2021 Jul 9;22(14):7395
info:eu-repo/grantAgreement/ES/2PE/PID2019-107188RB-C21
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv MDPI
publisher.none.fl_str_mv MDPI
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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