title: ENU mutagenesis reveals a novel phenotype of reduced limb strength in mice lacking fibrillin 2.
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.
  
  
  RESULTS
  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.
authors.affiliation: Mammalian Genetics of Disease Unit, School of Medicine, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Gaynor
authors.initials: G
authors.lastname: Miller
authors.forename: Monica
authors.initials: M
authors.lastname: Neilan
authors.forename: Ruth
authors.initials: R
authors.lastname: Chia
authors.forename: Nabeia
authors.initials: N
authors.lastname: Gheryani
authors.forename: Natalie
authors.initials: N
authors.lastname: Holt
authors.forename: Annabelle
authors.initials: A
authors.lastname: Charbit
authors.forename: Sara
authors.initials: S
authors.lastname: Wells
authors.forename: Valter
authors.initials: V
authors.lastname: Tucci
authors.forename: Zuzanne
authors.initials: Z
authors.lastname: Lalanne
authors.forename: Paul
authors.initials: P
authors.lastname: Denny
authors.forename: Elizabeth M C
authors.initials: EM
authors.lastname: Fisher
authors.forename: Michael
authors.initials: M
authors.lastname: Cheeseman
authors.forename: Graham N
authors.initials: GN
authors.lastname: Askew
authors.forename: T Neil
authors.initials: TN
authors.lastname: Dear
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D004252:DNA Mutational Analysis; D005038:Ethylnitrosourea / Q000633:toxicity; D005260:Female; D000071838:Fibrillin-1; D000071840:Fibrillin-2; D000071837:Fibrillins; D005838:Genotype; D006614:Hindlimb / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics*; D018908:Muscle Weakness / Q000235:genetics* / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D016296:Mutagenesis / Q000187:drug effects; D009154:Mutation; D010641:Phenotype; D013576:Syndactyly / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D054392:Adipokines
chemical_list: D005038:Ethylnitrosourea; D000071838:Fibrillin-1; D000071840:Fibrillin-2; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines; C000605723:FBN2 protein, human; C000605724:Fbn1 protein, mouse; C000605728:Fbn2 protein, mouse