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.

The mdx mutation in the 129/Sv background results in a milder phenotype: Transcriptome comparative analysis searching for the protective factors

“…The same results were observed in the test applied for the four limbs resistance and hind limb strength. Therefore, the observed results were the opposite of what was previously described [5] and which we were expecting. Considering the amelioration of the mdx phenotype in the 129/Sv background, we hypothesized that factors in this strain could act protecting the mdx 129 from the dystrophic effect.…”

“…Mainly because the mgΔ mutation for Marfan syndrome resulted in a more severe phenotype in the 129/Sv than in the C57BL background [5], while with the mdx mutation the result was inverse: a better phenotype in the 129/Sv than in the C57BL background. Histological analysis was not informative to differentiate the two mdx strains, since both mdx models presented a similar histopathological pattern in hind limbs as well as in diaphragm muscles.…”

Suppression of mTORC1 activation in acid-α-glucosidase-deficient cells and mice is ameliorated by leucine supplementation

“…Spontaneous locomotor activity was determined by indirect calorimetry using the Columbus Instruments Oxymax system, as described previously (33). Kyphosis was measured by X-ray image analysis, as described by Lima et al (11). Running capacity was determined as described by Zong et al (34).…”

Background differences in baseline and stimulated MMP levels influence abdominal aortic aneurysm susceptibility

“…15-19 The most widely used parent strains for the production of mutants in aneurysm research are C57Bl/6 and 129/SvEv mice. 7, 8, 20 In contrast to AAA, thoracic aortic aneurysms are associated with a number of known genetic mutations. Marfan syndrome (MFS) is caused by fibrillin-1 gene mutations that are responsible for thoracic aneurysm development.…”

“…21 Studies of animal models of MFS have shown that genetic background-related variations, C57Bl/6 or 129/SvEv, affect aneurysm formation, rupture, and lifespan of mice. 20, 22 The 129/SvEv genetic background is associated with more rapid aneurysm progression in MFS mice when compared to the C57Bl/6 background. 20 As in AAA, higher MMP-2 expression in the aorta of Marfan syndrome mice plays an important role in aneurysm formation.…”