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ENU Mutagenesis Reveals a Novel Phenotype of Reduced Limb Strength in Mice Lacking Fibrillin 2

BACKGROUND: Fibrillins 1 (FBN1) and 2 (FBN2) are components of microfibrils, microfilaments that are present in many connective tissues, either alone or in association with elastin. Marfan's syndrome and congenital contractural arachnodactyly (CCA) result from dominant mutations in the genes FB...

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Autores principales: Miller, Gaynor, Neilan, Monica, Chia, Ruth, Gheryani, Nabeia, Holt, Natalie, Charbit, Annabelle, Wells, Sara, Tucci, Valter, Lalanne, Zuzanne, Denny, Paul, Fisher, Elizabeth M. C., Cheeseman, Michael, Askew, Graham N., Dear, T. Neil
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2817753/
https://www.ncbi.nlm.nih.gov/pubmed/20161761
http://dx.doi.org/10.1371/journal.pone.0009137
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author Miller, Gaynor
Neilan, Monica
Chia, Ruth
Gheryani, Nabeia
Holt, Natalie
Charbit, Annabelle
Wells, Sara
Tucci, Valter
Lalanne, Zuzanne
Denny, Paul
Fisher, Elizabeth M. C.
Cheeseman, Michael
Askew, Graham N.
Dear, T. Neil
author_facet Miller, Gaynor
Neilan, Monica
Chia, Ruth
Gheryani, Nabeia
Holt, Natalie
Charbit, Annabelle
Wells, Sara
Tucci, Valter
Lalanne, Zuzanne
Denny, Paul
Fisher, Elizabeth M. C.
Cheeseman, Michael
Askew, Graham N.
Dear, T. Neil
author_sort Miller, Gaynor
collection PubMed
description BACKGROUND: Fibrillins 1 (FBN1) and 2 (FBN2) are components of microfibrils, microfilaments that are present in many connective tissues, either alone or in association with elastin. Marfan's syndrome and congenital contractural arachnodactyly (CCA) result from dominant mutations in the genes FBN1 and FBN2 respectively. Patients with both conditions often present with specific muscle atrophy or weakness, yet this has not been reported in the mouse models. In the case of Fbn1, this is due to perinatal lethality of the homozygous null mice making measurements of strength difficult. In the case of Fbn2, four different mutant alleles have been described in the mouse and in all cases syndactyly was reported as the defining phenotypic feature of homozygotes. METHODOLOGY/PRINCIPAL FINDINGS: As part of a large-scale N-ethyl-N-nitrosourea (ENU) mutagenesis screen, we identified a mouse mutant, Mariusz, which exhibited muscle weakness along with hindlimb syndactyly. We identified an amber nonsense mutation in Fbn2 in this mouse mutant. Examination of a previously characterised Fbn2-null mutant, Fbn2(fp), identified a similar muscle weakness phenotype. The two Fbn2 mutant alleles complement each other confirming that the weakness is the result of a lack of Fbn2 activity. Skeletal muscle from mutants proved to be abnormal with higher than average numbers of fibres with centrally placed nuclei, an indicator that there are some regenerating muscle fibres. Physiological tests indicated that the mutant muscle produces significantly less maximal force, possibly as a result of the muscles being relatively smaller in Mariusz mice. CONCLUSIONS: These findings indicate that Fbn2 is involved in integrity of structures required for strength in limb movement. As human patients with mutations in the fibrillin genes FBN1 and FBN2 often present with muscle weakness and atrophy as a symptom, Fbn2-null mice will be a useful model for examining this aspect of the disease process further.
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spelling pubmed-28177532010-02-17 ENU Mutagenesis Reveals a Novel Phenotype of Reduced Limb Strength in Mice Lacking Fibrillin 2 Miller, Gaynor Neilan, Monica Chia, Ruth Gheryani, Nabeia Holt, Natalie Charbit, Annabelle Wells, Sara Tucci, Valter Lalanne, Zuzanne Denny, Paul Fisher, Elizabeth M. C. Cheeseman, Michael Askew, Graham N. Dear, T. Neil PLoS One Research Article BACKGROUND: Fibrillins 1 (FBN1) and 2 (FBN2) are components of microfibrils, microfilaments that are present in many connective tissues, either alone or in association with elastin. Marfan's syndrome and congenital contractural arachnodactyly (CCA) result from dominant mutations in the genes FBN1 and FBN2 respectively. Patients with both conditions often present with specific muscle atrophy or weakness, yet this has not been reported in the mouse models. In the case of Fbn1, this is due to perinatal lethality of the homozygous null mice making measurements of strength difficult. In the case of Fbn2, four different mutant alleles have been described in the mouse and in all cases syndactyly was reported as the defining phenotypic feature of homozygotes. METHODOLOGY/PRINCIPAL FINDINGS: As part of a large-scale N-ethyl-N-nitrosourea (ENU) mutagenesis screen, we identified a mouse mutant, Mariusz, which exhibited muscle weakness along with hindlimb syndactyly. We identified an amber nonsense mutation in Fbn2 in this mouse mutant. Examination of a previously characterised Fbn2-null mutant, Fbn2(fp), identified a similar muscle weakness phenotype. The two Fbn2 mutant alleles complement each other confirming that the weakness is the result of a lack of Fbn2 activity. Skeletal muscle from mutants proved to be abnormal with higher than average numbers of fibres with centrally placed nuclei, an indicator that there are some regenerating muscle fibres. Physiological tests indicated that the mutant muscle produces significantly less maximal force, possibly as a result of the muscles being relatively smaller in Mariusz mice. CONCLUSIONS: These findings indicate that Fbn2 is involved in integrity of structures required for strength in limb movement. As human patients with mutations in the fibrillin genes FBN1 and FBN2 often present with muscle weakness and atrophy as a symptom, Fbn2-null mice will be a useful model for examining this aspect of the disease process further. Public Library of Science 2010-02-09 /pmc/articles/PMC2817753/ /pubmed/20161761 http://dx.doi.org/10.1371/journal.pone.0009137 Text en Miller 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, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Miller, Gaynor
Neilan, Monica
Chia, Ruth
Gheryani, Nabeia
Holt, Natalie
Charbit, Annabelle
Wells, Sara
Tucci, Valter
Lalanne, Zuzanne
Denny, Paul
Fisher, Elizabeth M. C.
Cheeseman, Michael
Askew, Graham N.
Dear, T. Neil
ENU Mutagenesis Reveals a Novel Phenotype of Reduced Limb Strength in Mice Lacking Fibrillin 2
title ENU Mutagenesis Reveals a Novel Phenotype of Reduced Limb Strength in Mice Lacking Fibrillin 2
title_full ENU Mutagenesis Reveals a Novel Phenotype of Reduced Limb Strength in Mice Lacking Fibrillin 2
title_fullStr ENU Mutagenesis Reveals a Novel Phenotype of Reduced Limb Strength in Mice Lacking Fibrillin 2
title_full_unstemmed ENU Mutagenesis Reveals a Novel Phenotype of Reduced Limb Strength in Mice Lacking Fibrillin 2
title_short ENU Mutagenesis Reveals a Novel Phenotype of Reduced Limb Strength in Mice Lacking Fibrillin 2
title_sort enu mutagenesis reveals a novel phenotype of reduced limb strength in mice lacking fibrillin 2
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2817753/
https://www.ncbi.nlm.nih.gov/pubmed/20161761
http://dx.doi.org/10.1371/journal.pone.0009137
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