A 25-year-old woman with Marfan syndrome is found to have aortic root dilation. The molecular defect in Marfan syndrome involves which protein, and how does this defect mechanistically cause cardiovascular manifestations?

• A Collagen type I mutation causing defective cross-linking of aortic wall collagen fibers
• B Fibrillin-1 mutation causing reduced sequestration of TGF-beta, which promotes smooth muscle cell apoptosis and matrix metalloproteinase activation in the aortic wall ✓
• C Elastin mutation directly weakening the aortic media
• D ELN gene haploinsufficiency causing supravalvular aortic stenosis

Explanation

Marfan syndrome results from mutations in FBN1 (fibrillin-1), a glycoprotein of the extracellular matrix that normally sequesters latent TGF-beta. Defective fibrillin-1 leads to excess free TGF-beta signaling, which stimulates MMP expression, impairs smooth muscle cell survival, and promotes cystic medial degeneration of the aorta. This mechanistic insight is the basis for using TGF-beta pathway blockers (losartan) alongside beta-blockers to slow aortic dilation. Collagen I mutations cause osteogenesis imperfecta.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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