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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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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 |
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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 |
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