A new mouse model for marfan syndrome presents phenotypic variability associated with the genetic background and overall levels of Fbn1 expression |
| |
Authors: | 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 |
| |
Affiliation: | Laboratório de Genética Molecular do Departamento de Genética e Biologia Evolutiva, Universidade de S?o Paulo, S?o Paulo, Brazil. |
| |
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. |
| |
Keywords: | |
本文献已被 PubMed 等数据库收录! |
|