Abstract
Marfan syndrome (MFS) is an autosomal dominant disease of the connective tissue, affecting mostly the skeletal, ocular and cardiovascular systems, caused by mutations in the FBN1 gene. The existence of modifier genes has been postulated based on the wide clinical variability of manifestations in patients, even among those with the same FBN1 mutation. Although isogenic mouse models of the disease were fundamental in dissecting the molecular mechanism of pathogenesis, they do not address the effect of genetic background on the disease phenotype. Here, we use a new mouse model, mgΔloxPneo, which presents different phenotype severity dependent on the genetic backgrounds, to identify genes involved in modulating MFS phenotype. F2 heterozygotes showed wide phenotypic variability, with no correlations between phenotypic severities of the different affected systems, indicating that each has its specific set of modifier genes. Individual analysis of the phenotypes, with SNP microarrays, identified two suggestive QTL each to the cardiovascular and skeletal, and one significant QTL to the skeletal phenotype. Epistatic interactions between the QTL account for 47.4% and 53.5% of variation in the skeletal and cardiovascular phenotypes, respectively. This is the first study that maps modifier loci for MFS, showing the complex genetic architecture underlying the disease.
Highlights
Marfan syndrome (MFS, OMIM #154700) is an autosomal dominant disorder of the connective tissue characterized by skeletal, ocular, cardiovascular, skin and pulmonary manifestations[1]
Based on the genotypes of the closest SNP to the estimated position of each quantitative trait loci (QTL), we identified the dominance of QTL Krq[1], Krq[2], and Awtq[2], with the effect of the 129 allele dominating the B6 allele in Krq[1] and Awtq[2], and B6 dominating 129 in Krq[2] (Fig. 4); Awtq[1] demonstrated an additive effect
By including two mouse strains, B6 and 129, we were able to produce a murine model of MFS with wide variation in phenotypic severity in F2 animals, a scenario similar to the broad spectrum of human phenotypic severity among skeletal, pulmonary, and cardiovascular systems
Summary
Marfan syndrome (MFS, OMIM #154700) is an autosomal dominant disorder of the connective tissue characterized by skeletal, ocular, cardiovascular, skin and pulmonary manifestations[1]. The disease affects 1–2/10,000 individuals and is caused by mutations in the FBN1 gene that encodes fibrillin-1, the major structural component of microfibrils (reviewed in[2]). It is still not clear whether FBN1 mutations lead to disease due to a dominant negative effect and/or to haploinsufficiency[3], it is well established that fibrillin-1 containing microfibrils control the bioavailability of active TGF-β in the matrix, and that FBN1 mutations lead to pathologically increased TFG-β signaling[4]. In 2010, Lima et al reported the mg∆ loxPneo mouse model of MFS that develops skeletal, cardiovascular, and pulmonary alterations with different severities and age of onset between the two isogenic strains 129/Sv (129) and. We identify two quantitative trait loci (QTL) with suggestive linkages to the cardiovascular and skeletal phenotypes each, and one QTL with significant linkage to the skeletal phenotype, and show epistatic interactions among them
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