A 30-year-old man with Marfan syndrome carries a heterozygous missense FBN1 mutation. The mutant fibrillin-1 causes disease through a dominant-negative mechanism. This means:
- A The mutant allele reduces fibrillin-1 levels by 50%, insufficient for structural integrity (haploinsufficiency)
- B The mutant fibrillin-1 protein disrupts the function of wild-type fibrillin-1 in microfibrils, compounding the 50% reduction in a disproportionate effect ✓
- C Mutant fibrillin-1 sequesters TGF-β excessively, paradoxically increasing TGF-β signaling
- D The FBN1 mutation causes de novo gain-of-function activation of PI3K-AKT pathway
Explanation
Most FBN1 mutations in Marfan syndrome act by dominant-negative mechanism: the mutant fibrillin-1 protein is incorporated into microfibrils but disrupts the structure of the entire microfibril polymer, causing degradation of both mutant and wild-type fibrillin-1. This explains why heterozygous individuals (50% mutant allele) have severe phenotypes disproportionate to simple haploinsufficiency. Additionally, disrupted microfibrils fail to sequester TGF-β, leading to excess free TGF-β signaling (via ALK5) in the aortic wall, contributing to aortic root dilation — this is the basis for losartan (TGF-β antagonism) therapy in Marfan.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.