A newborn with features of Marfan syndrome is found to have a mutation in the FBN1 gene encoding fibrillin-1. Beyond causing structural weakness of the extracellular matrix, fibrillin-1 deficiency contributes to Marfan pathogenesis through which additional molecular mechanism?

• A Disruption of elastic fibre crosslinking via lysyl oxidase inhibition
• B Upregulation of MMP-1 and MMP-3 directly by fibrillin-1 fragments
• C Loss of fibrillin-1 causing collagen type I haploinsufficiency
• D Excess free TGF-β signalling due to loss of fibrillin-1–mediated sequestration of latent TGF-β in the ECM ✓

Explanation

Fibrillin-1 microfibrils normally sequester latent TGF-β complexes (large latent complex/LTBP) in the ECM, preventing their activation. In Marfan syndrome, reduced functional fibrillin-1 causes excess free TGF-β signalling, which dysregulates aortic smooth muscle cell homeostasis, promotes matrix metalloproteinase expression, and causes abnormal elastic fibre organisation — contributing to aortic root dilation beyond simple structural weakness. This mechanistic insight led to clinical trials of losartan (an AT1R antagonist that reduces TGF-β signalling) as a disease-modifying treatment in Marfan syndrome.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.