Identification of Loci Modulating the Cardiovascular and Skeletal Phenotypes of Marfan Syndrome in Mice.

Marfan syndrome (MFS, OMIM #154700) is an autosomal dominant disorder of the connective tissue characterized by skeletal, ocular, cardiovascular, skin and pulmonary manifestations1. 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 in2). Although it is still not clear whether FBN1 mutations lead to disease due to a dominant negative effect and/or to haploinsufficiency3, 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 signaling4. In fact, inhibition of TGF-β signaling in mouse models of MFS prevents the development of pulmonary and cardiovascular phenotypes, regardless of the presence of mutant fibrillin-15. Despite its complete penetrance, one trademark of MFS is its wide clinical variability6, where even siblings with the same mutation can display different age of onset and/or disease severity. The diversity of manifestations of MFS and lack of identifiable phenotype-genotype correlations suggest the existence of modifier genes7. Indeed, given the complex molecular pathogenesis of MFS and its pleiotropy, polymorphisms in a number of genes may modulate the effect of FBN1 mutations in the different affected systems. 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 C57BL/6 (B6). These spectra of disease manifestations indicate that allelic differences between the two strains modulate MFS phenotype in a fashion more similar to human MFS than past isogenic murine models of the disease8. We used the mg∆loxPneo model to map loci associated with phenotype severity in MFS. By analysis of F1 and F2 crossed between B6 and 129 heterozygous for the Fbn1 mutation, we show that each affected system has its own set of modifier genes. Moreover, 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.