Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Ugartondo, Nerea, Martínez-Gil, Núria, Esteve, Mònica, Garcia-Giralt, Natàlia, Roca-Ayats, Neus, Ovejero, Diana, Nogués, Xavier, Díez-Pérez, Adolfo, Rabionet, Raquel, Grinberg, Daniel, Balcells, Susanna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303772/
https://www.ncbi.nlm.nih.gov/pubmed/34299011
http://dx.doi.org/10.3390/ijms22147395
_version_ 1783727169701150720
author Ugartondo, Nerea
Martínez-Gil, Núria
Esteve, Mònica
Garcia-Giralt, Natàlia
Roca-Ayats, Neus
Ovejero, Diana
Nogués, Xavier
Díez-Pérez, Adolfo
Rabionet, Raquel
Grinberg, Daniel
Balcells, Susanna
author_facet Ugartondo, Nerea
Martínez-Gil, Núria
Esteve, Mònica
Garcia-Giralt, Natàlia
Roca-Ayats, Neus
Ovejero, Diana
Nogués, Xavier
Díez-Pérez, Adolfo
Rabionet, Raquel
Grinberg, Daniel
Balcells, Susanna
author_sort Ugartondo, Nerea
collection PubMed
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.
format Online
Article
Text
id pubmed-8303772
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-83037722021-07-25 Functional Analyses of Four CYP1A1 Missense Mutations Present in Patients with Atypical Femoral Fractures Ugartondo, Nerea Martínez-Gil, Núria Esteve, Mònica Garcia-Giralt, Natàlia Roca-Ayats, Neus Ovejero, Diana Nogués, Xavier Díez-Pérez, Adolfo Rabionet, Raquel Grinberg, Daniel Balcells, Susanna Int J Mol Sci Article 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. MDPI 2021-07-09 /pmc/articles/PMC8303772/ /pubmed/34299011 http://dx.doi.org/10.3390/ijms22147395 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/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 (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Ugartondo, Nerea
Martínez-Gil, Núria
Esteve, Mònica
Garcia-Giralt, Natàlia
Roca-Ayats, Neus
Ovejero, Diana
Nogués, Xavier
Díez-Pérez, Adolfo
Rabionet, Raquel
Grinberg, Daniel
Balcells, Susanna
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
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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8303772/
https://www.ncbi.nlm.nih.gov/pubmed/34299011
http://dx.doi.org/10.3390/ijms22147395
work_keys_str_mv AT ugartondonerea functionalanalysesoffourcyp1a1missensemutationspresentinpatientswithatypicalfemoralfractures
AT martinezgilnuria functionalanalysesoffourcyp1a1missensemutationspresentinpatientswithatypicalfemoralfractures
AT estevemonica functionalanalysesoffourcyp1a1missensemutationspresentinpatientswithatypicalfemoralfractures
AT garciagiraltnatalia functionalanalysesoffourcyp1a1missensemutationspresentinpatientswithatypicalfemoralfractures
AT rocaayatsneus functionalanalysesoffourcyp1a1missensemutationspresentinpatientswithatypicalfemoralfractures
AT ovejerodiana functionalanalysesoffourcyp1a1missensemutationspresentinpatientswithatypicalfemoralfractures
AT noguesxavier functionalanalysesoffourcyp1a1missensemutationspresentinpatientswithatypicalfemoralfractures
AT diezperezadolfo functionalanalysesoffourcyp1a1missensemutationspresentinpatientswithatypicalfemoralfractures
AT rabionetraquel functionalanalysesoffourcyp1a1missensemutationspresentinpatientswithatypicalfemoralfractures
AT grinbergdaniel functionalanalysesoffourcyp1a1missensemutationspresentinpatientswithatypicalfemoralfractures
AT balcellssusanna functionalanalysesoffourcyp1a1missensemutationspresentinpatientswithatypicalfemoralfractures