%0 Journal Article
%T A New Mouse Model for Marfan Syndrome Presents Phenotypic Variability Associated with the Genetic Background and Overall Levels of Fbn1 Expression
%A Bruno L. Lima
%A Enrico J. C. Santos
%A Gustavo R. Fernandes
%A Christian Merkel
%A Marco R. B. Mello
%A Juliana P. A. Gomes
%A Marina Soukoyan
%A Alexandre Kerkis
%A Silvia M. G. Massironi
%A Jos¨¦ A. Visintin
%A Lygia V. Pereira
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0014136
%X Marfan syndrome is an autosomal dominant disease of connective tissue caused by mutations in the fibrillin-1 encoding gene FBN1. Patients present cardiovascular, ocular and skeletal manifestations, and although being fully penetrant, MFS is characterized by a wide clinical variability both within and between families. Here we describe a new mouse model of MFS that recapitulates the clinical heterogeneity of the syndrome in humans. Heterozygotes for the mutant Fbn1 allele mg¦¤loxPneo, carrying the same internal deletion of exons 19¨C24 as the mg¦¤ mouse model, present defective microfibrillar deposition, emphysema, deterioration of aortic wall and kyphosis. However, the onset of a clinical phenotypes is earlier in the 129/Sv than in C57BL/6 background, indicating the existence of genetic modifiers of MFS between these two mouse strains. In addition, we characterized a wide clinical variability within the 129/Sv congenic heterozygotes, suggesting involvement of epigenetic factors in disease severity. Finally, we show a strong negative correlation between overall levels of Fbn1 expression and the severity of the phenotypes, corroborating the suggested protective role of normal fibrillin-1 in MFS pathogenesis, and supporting the development of therapies based on increasing Fbn1 expression.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0014136