title: A new mouse model for marfan syndrome presents phenotypic variability associated with the genetic background and overall levels of Fbn1 expression.
abstract: 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 mgΔloxPneo, carrying the same internal deletion of exons 19-24 as the mgΔ 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.
authors.affiliation: Laboratório de Genética Molecular do Departamento de Genética e Biologia Evolutiva, Universidade de São Paulo, São Paulo, Brazil.
authors.forename: Bruno L
authors.initials: BL
authors.lastname: Lima
authors.forename: Enrico J C
authors.initials: EJ
authors.lastname: Santos
authors.forename: Gustavo R
authors.initials: GR
authors.lastname: Fernandes
authors.forename: Christian
authors.initials: C
authors.lastname: Merkel
authors.forename: Marco R B
authors.initials: MR
authors.lastname: Mello
authors.forename: Juliana P A
authors.initials: JP
authors.lastname: Gomes
authors.forename: Marina
authors.initials: M
authors.lastname: Soukoyan
authors.forename: Alexandre
authors.initials: A
authors.lastname: Kerkis
authors.forename: Silvia M G
authors.initials: SM
authors.lastname: Massironi
authors.forename: José A
authors.initials: JA
authors.lastname: Visintin
authors.forename: Lygia V
authors.initials: LV
authors.lastname: Pereira
mesh_terms: D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D000071838:Fibrillin-1; D000071837:Fibrillins; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D008382:Marfan Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; C000605722:FBN1 protein, human; D054392:Adipokines; C000605724:Fbn1 protein, mouse