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FBXO7 sensitivity of phenotypic traits elucidated by a hypomorphic allele
FBXO7 encodes an F box containing protein that interacts with multiple partners to facilitate numerous cellular processes and has a canonical role as part of an SCF E3 ubiquitin ligase complex. Mutation of FBXO7 is responsible for an early onset Parkinsonian pyramidal syndrome and genome-wide associ...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402633/ https://www.ncbi.nlm.nih.gov/pubmed/30840666 http://dx.doi.org/10.1371/journal.pone.0212481 |
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author | Ballesteros Reviriego, Carmen Clare, Simon Arends, Mark J. Cambridge, Emma L. Swiatkowska, Agnieszka Caetano, Susana Abu-Helil, Bushra Kane, Leanne Harcourt, Katherine Goulding, David A. Gleeson, Diane Ryder, Edward Doe, Brendan White, Jacqueline K. van der Weyden, Louise Dougan, Gordon Adams, David J. Speak, Anneliese O. |
author_facet | Ballesteros Reviriego, Carmen Clare, Simon Arends, Mark J. Cambridge, Emma L. Swiatkowska, Agnieszka Caetano, Susana Abu-Helil, Bushra Kane, Leanne Harcourt, Katherine Goulding, David A. Gleeson, Diane Ryder, Edward Doe, Brendan White, Jacqueline K. van der Weyden, Louise Dougan, Gordon Adams, David J. Speak, Anneliese O. |
author_sort | Ballesteros Reviriego, Carmen |
collection | PubMed |
description | FBXO7 encodes an F box containing protein that interacts with multiple partners to facilitate numerous cellular processes and has a canonical role as part of an SCF E3 ubiquitin ligase complex. Mutation of FBXO7 is responsible for an early onset Parkinsonian pyramidal syndrome and genome-wide association studies have linked variants in FBXO7 to erythroid traits. A putative orthologue in Drosophila, nutcracker, has been shown to regulate the proteasome, and deficiency of nutcracker results in male infertility. Therefore, we reasoned that modulating Fbxo7 levels in a murine model could provide insights into the role of this protein in mammals. We used a targeted gene trap model which retained 4–16% residual gene expression and assessed the sensitivity of phenotypic traits to gene dosage. Fbxo7 hypomorphs showed regenerative anaemia associated with a shorter erythrocyte half-life, and male mice were infertile. Alterations to T cell phenotypes were also observed, which intriguingly were both T cell intrinsic and extrinsic. Hypomorphic mice were also sensitive to infection with Salmonella, succumbing to a normally sublethal challenge. Despite these phenotypes, Fbxo7 hypomorphs were produced at a normal Mendelian ratio with a normal lifespan and no evidence of neurological symptoms. These data suggest that erythrocyte survival, T cell development and spermatogenesis are particularly sensitive to Fbxo7 gene dosage. |
format | Online Article Text |
id | pubmed-6402633 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-64026332019-03-17 FBXO7 sensitivity of phenotypic traits elucidated by a hypomorphic allele Ballesteros Reviriego, Carmen Clare, Simon Arends, Mark J. Cambridge, Emma L. Swiatkowska, Agnieszka Caetano, Susana Abu-Helil, Bushra Kane, Leanne Harcourt, Katherine Goulding, David A. Gleeson, Diane Ryder, Edward Doe, Brendan White, Jacqueline K. van der Weyden, Louise Dougan, Gordon Adams, David J. Speak, Anneliese O. PLoS One Research Article FBXO7 encodes an F box containing protein that interacts with multiple partners to facilitate numerous cellular processes and has a canonical role as part of an SCF E3 ubiquitin ligase complex. Mutation of FBXO7 is responsible for an early onset Parkinsonian pyramidal syndrome and genome-wide association studies have linked variants in FBXO7 to erythroid traits. A putative orthologue in Drosophila, nutcracker, has been shown to regulate the proteasome, and deficiency of nutcracker results in male infertility. Therefore, we reasoned that modulating Fbxo7 levels in a murine model could provide insights into the role of this protein in mammals. We used a targeted gene trap model which retained 4–16% residual gene expression and assessed the sensitivity of phenotypic traits to gene dosage. Fbxo7 hypomorphs showed regenerative anaemia associated with a shorter erythrocyte half-life, and male mice were infertile. Alterations to T cell phenotypes were also observed, which intriguingly were both T cell intrinsic and extrinsic. Hypomorphic mice were also sensitive to infection with Salmonella, succumbing to a normally sublethal challenge. Despite these phenotypes, Fbxo7 hypomorphs were produced at a normal Mendelian ratio with a normal lifespan and no evidence of neurological symptoms. These data suggest that erythrocyte survival, T cell development and spermatogenesis are particularly sensitive to Fbxo7 gene dosage. Public Library of Science 2019-03-06 /pmc/articles/PMC6402633/ /pubmed/30840666 http://dx.doi.org/10.1371/journal.pone.0212481 Text en © 2019 Ballesteros Reviriego et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Ballesteros Reviriego, Carmen Clare, Simon Arends, Mark J. Cambridge, Emma L. Swiatkowska, Agnieszka Caetano, Susana Abu-Helil, Bushra Kane, Leanne Harcourt, Katherine Goulding, David A. Gleeson, Diane Ryder, Edward Doe, Brendan White, Jacqueline K. van der Weyden, Louise Dougan, Gordon Adams, David J. Speak, Anneliese O. FBXO7 sensitivity of phenotypic traits elucidated by a hypomorphic allele |
title | FBXO7 sensitivity of phenotypic traits elucidated by a hypomorphic allele |
title_full | FBXO7 sensitivity of phenotypic traits elucidated by a hypomorphic allele |
title_fullStr | FBXO7 sensitivity of phenotypic traits elucidated by a hypomorphic allele |
title_full_unstemmed | FBXO7 sensitivity of phenotypic traits elucidated by a hypomorphic allele |
title_short | FBXO7 sensitivity of phenotypic traits elucidated by a hypomorphic allele |
title_sort | fbxo7 sensitivity of phenotypic traits elucidated by a hypomorphic allele |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402633/ https://www.ncbi.nlm.nih.gov/pubmed/30840666 http://dx.doi.org/10.1371/journal.pone.0212481 |
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