An integrative systems approach identifies novel candidates in Marfan syndrome‐related pathophysiology

Abstract

Marfan syndrome ( MFS ) is an autosomal dominant genetic disorder caused by mutations in the FBN 1 gene. Although many peripheral tissues are affected, aortic complications, such as dilation, dissection and rupture, are the leading causes of MFS ‐related mortality. Aberrant TGF ‐beta signalling plays a major role in the pathophysiology of MFS . However, the contributing mechanisms are still poorly understood. Here, we aimed at identifying novel aorta‐specific pathways involved in the pathophysiology of MFS . For this purpose, we employed the Fbn1 under‐expressing mgR/mgR mouse model of MFS . We performed RNA ‐sequencing of aortic tissues of 9‐week‐old mgR/mgR mice compared with wild‐type ( WT ) mice. With a false discovery rate <5%, our analysis revealed 248 genes to be differentially regulated including 20 genes previously unrelated with MFS ‐related pathology. Among these, we identified Igfbp2 , Ccl8 , Spp1 , Mylk2 , Mfap4 , Dsp and H19 . We confirmed the expression of regulated genes by quantitative real‐time PCR . Pathway classification revealed transcript signatures involved in chemokine signalling, cardiac muscle contraction, dilated and hypertrophic cardiomyopathy. Furthermore, our immunoblot analysis of aortic tissues revealed altered regulation of pS mad2 signalling, Perk1/2, Igfbp2, Mfap4, Ccl8 and Mylk2 protein levels in mgR/mgR vs WT mice. Together, our integrative systems approach identified several novel factors associated with MFS ‐aortic‐specific pathophysiology that might offer potential novel therapeutic targets for MFS .

Numerical knockouts–In silico assessment of factors predisposing to thoracic aortic aneurysms

“…[ 11 , 12 ]). Indeed, genetic analyses reveal hundreds of differentially expressed genes even in the case of a targeted mutation to a single gene (e.g., [ 13 , 14 ]), suggesting that additional collateral or compensatory changes can complicate interpretation further.…”

Rare Causes of Arterial Hypertension and Thoracic Aortic Aneurysms—A Case-Based Review

“…Last, but not least, other genes may contribute to hypertension in PRKG1 mutations. For instance, a KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis of differentially regulated genes in Marfan syndrome revealed other genes involved in the cGMP–PKG signaling pathways, including Irs2, Irs3, (which encode insulin receptor substrates) and Adcy7 (encoding adenylate cyclase 7) involved in the pathogenesis of hypertension [ 56 ]. Additionally, in hypertensive patients with TAA, the variant allele of THBS2 encoding the thrombospondin-2 (which may lead to an increase in metalloproteinase MMP-2) is a risk factor for TAA [ 57 ].…”

Assessment of Bones Deficient in Fibrillin-1 Microfibrils Reveals Pronounced Sex Differences

“…In addition, considering previous findings in relation to the heart—where the response to treatment may differ significantly between the sexes [23,24] or between different genetic backgrounds [25]—and the contribution of multiple genetic variations to disease development and drug responses [26,27], it would be of interest to determine the role of sex in bone remodeling using different animal models of MFS. Furthermore, although the role of aberrant TGFβ signaling in the pathophysiology of MFS is well established, there is an incomplete understanding of the contributing mechanisms [28], particularly in MFS-associated skeletal pathophysiology. Moreover, the objective of this analysis was focused on comparing male and female Fbn1 mgR/mgR mice directly and not with wild-type mice.…”