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A new mouse model for marfan syndrome presents phenotypic variability associated with the genetic background and overall levels of Fbn1 expression

Lima, Bruno L ; Santos, Enrico J C ; Fernandes, Gustavo R ; Merkel, Christian ; Mello, Marco R B ; Gomes, Juliana P A ; Soukoyan, Marina ; Kerkis, Alexandre ; Massironi, Silvia M G ; Visintin, José A ; Pereira, Lygia V Nogales-Gadea, Gisela

PloS one, 2010-11, Vol.5 (11), p.e14136-e14136 [Periódico revisado por pares]

United States: Public Library of Science

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A new mouse model for marfan syndrome presents phenotypic variability associated with the genetic background and overall levels of Fbn1 expression
Autor: Lima, Bruno L ; Santos, Enrico J C ; Fernandes, Gustavo R ; Merkel, Christian ; Mello, Marco R B ; Gomes, Juliana P A ; Soukoyan, Marina ; Kerkis, Alexandre ; Massironi, Silvia M G ; Visintin, José A ; Pereira, Lygia V
Nogales-Gadea, Gisela
Assuntos: Analysis ; Animals ; Aorta ; Base Sequence ; Bone diseases ; Cardiovascular Disorders/Vascular Biology ; Cells, Cultured ; Connective tissues ; Deoxyribonucleic acid ; Disease ; Disease Models, Animal ; DNA ; Embryo, Mammalian - cytology ; Embryo, Mammalian - metabolism ; Emphysema ; Epigenetics ; Exons ; Fibrillin ; Fibrillin-1 ; Fibrillins ; Fibroblasts - cytology ; Fibroblasts - metabolism ; Fluorescent Antibody Technique ; Gene Expression ; Genetic aspects ; Genetic disorders ; Genetic variability ; Genetics ; Genetics and Genomics ; Genetics and Genomics/Disease Models ; Genetics and Genomics/Epigenetics ; Genetics and Genomics/Gene Expression ; Genotype ; Heterozygotes ; Humans ; Kyphosis ; Laboratories ; Marfan syndrome ; Marfan Syndrome - genetics ; Marfan Syndrome - metabolism ; Marfan Syndrome - pathology ; Marfan's syndrome ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Knockout ; Microfilament Proteins - genetics ; Microfilament Proteins - metabolism ; Mutation ; Pathogenesis ; Personal computers ; Phenotype ; Proteins ; Reverse Transcriptase Polymerase Chain Reaction ; Stem cells ; Trends ; Variability
É parte de: PloS one, 2010-11, Vol.5 (11), p.e14136-e14136
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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Conceived and designed the experiments: BLL EJCS SMGM JAV LVP. Performed the experiments: BLL EJCS GRF CAM MRBM MS AK SMGM JPAG LVP. Analyzed the data: BLL EJCS GRF CAM MRBM SMGM JPAG JAV LVP. Wrote the paper: BLL LVP.
Current address: Celltrovet – Applied Genetics, Veterinary Activities Ltda., São Paulo, Brazil
Current address: Instituto do Coração e Fundação Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
Current address: Departamento de Reprodução e Avaliação Animal, Instituto de Zootecnia da Universidade Federal Rural do Rio de Janeiro, Seropédica, Brazil
Descrição: 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.
Editor: United States: Public Library of Science
Idioma: Inglês

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A new mouse model for marfan syndrome presents phenotypic variability associated with the genetic background and overall levels of Fbn1 expression

Lima, Bruno L ; Santos, Enrico J C ; Fernandes, Gustavo R ; Merkel, Christian ; Mello, Marco R B ; Gomes, Juliana P A ; Soukoyan, Marina ; Kerkis, Alexandre ; Massironi, Silvia M G ; Visintin, José A ; Pereira, Lygia V Nogales-Gadea, Gisela

United States: Public Library of Science

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