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

Miller, G; Neilan, M; Chia, R; Gheryani, N; Holt, N; Charbit, A; Wells, S; ... Dear, TN; + view all (2010) ENU Mutagenesis Reveals a Novel Phenotype of Reduced Limb Strength in Mice Lacking Fibrillin 2. PLOS ONE , 5 (2) , Article e9137. 10.1371/journal.pone.0009137. Green open access

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Abstract

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.

Type: Article
Title: ENU Mutagenesis Reveals a Novel Phenotype of Reduced Limb Strength in Mice Lacking Fibrillin 2
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pone.0009137
Publisher version: http://dx.doi.org/10.1371/journal.pone.0009137
Language: English
Additional information: © 2010 Miller et al. 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 credited. The authors have no support or funding to report.
Keywords: MARFAN-SYNDROME, EXTRACELLULAR MICROFIBRILS, SKELETAL-MUSCLES, MOUSE, GENE, MUTATIONS, DRIVEN, SCREENS, FBN2, SY
UCL classification: UCL > School of Life and Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology
UCL > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Neurology > Neurodegenerative Diseases
UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Centre for Cardiovascular Genetics
URI: http://discovery.ucl.ac.uk/id/eprint/126658
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