ENU mutagenesis reveals a novel phenotype of reduced limb strength in mice lacking fibrillin 2.

<h4>Background</h4>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 mutati...

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Autores principales:	Gaynor Miller, Monica Neilan, Ruth Chia, Nabeia Gheryani, Natalie Holt, Annabelle Charbit, Sara Wells, Valter Tucci, Zuzanne Lalanne, Paul Denny, Elizabeth M C Fisher, Michael Cheeseman, Graham N Askew, T Neil Dear
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/095c5bd1ac0c4528b8de42f504717eeb
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spelling	oai:doaj.org-article:095c5bd1ac0c4528b8de42f504717eeb2021-11-25T06:25:58ZENU mutagenesis reveals a novel phenotype of reduced limb strength in mice lacking fibrillin 2.1932-620310.1371/journal.pone.0009137https://doaj.org/article/095c5bd1ac0c4528b8de42f504717eeb2010-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20161761/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions</h4>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.Gaynor MillerMonica NeilanRuth ChiaNabeia GheryaniNatalie HoltAnnabelle CharbitSara WellsValter TucciZuzanne LalannePaul DennyElizabeth M C FisherMichael CheesemanGraham N AskewT Neil DearPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 2, p e9137 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Gaynor Miller Monica Neilan Ruth Chia Nabeia Gheryani Natalie Holt Annabelle Charbit Sara Wells Valter Tucci Zuzanne Lalanne Paul Denny Elizabeth M C Fisher Michael Cheeseman Graham N Askew T Neil Dear ENU mutagenesis reveals a novel phenotype of reduced limb strength in mice lacking fibrillin 2.
description	<h4>Background</h4>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.<h4>Methodology/principal findings</h4>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.<h4>Conclusions</h4>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.
format	article
author	Gaynor Miller Monica Neilan Ruth Chia Nabeia Gheryani Natalie Holt Annabelle Charbit Sara Wells Valter Tucci Zuzanne Lalanne Paul Denny Elizabeth M C Fisher Michael Cheeseman Graham N Askew T Neil Dear
author_facet	Gaynor Miller Monica Neilan Ruth Chia Nabeia Gheryani Natalie Holt Annabelle Charbit Sara Wells Valter Tucci Zuzanne Lalanne Paul Denny Elizabeth M C Fisher Michael Cheeseman Graham N Askew T Neil Dear
author_sort	Gaynor Miller
title	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_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_sort	enu mutagenesis reveals a novel phenotype of reduced limb strength in mice lacking fibrillin 2.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/095c5bd1ac0c4528b8de42f504717eeb
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ENU mutagenesis reveals a novel phenotype of reduced limb strength in mice lacking fibrillin 2.

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