Transthyretin (TTR) amyloidosis (ATTR) causes restrictive cardiomyopathy. Val122Ile (V142I in new nomenclature) is the most common pathogenic variant in Black patients. What is the mechanism by which mutant TTR forms amyloid fibrils different from wild-type TTR?
- A Mutant TTR has enhanced binding to retinol, preventing normal secretion and causing intrahepatic aggregation
- B Mutant TTR activates the serum amyloid A (SAA) promoter, increasing circulating SAA levels that deposit as AA amyloid
- C Mutant TTR has reduced thermodynamic stability, causing tetramer dissociation to monomers that misfold and aggregate into amyloid fibrils at normal body temperature ✓
- D Mutant TTR loses its thyroxine-binding capacity, redirecting monomer folding toward beta-sheet-rich structures
Explanation
TTR normally exists as a stable homotetramer. Hereditary and wild-type ATTR amyloidogenesis share the same mechanism: tetramer dissociation is the rate-limiting step. Pathogenic mutations (Val122Ile/V142I, Val30Met/V50M) destabilize the tetramer-dimer interface, lowering the energy barrier for dissociation into monomers. These monomers partially unfold, exposing hydrophobic regions that nucleate beta-sheet-rich protofibrils and amyloid fibrils. TTR stabilizers (tafamidis, diflunisal) work by binding the thyroxine pocket, kinetically stabilizing the tetramer and preventing dissociation — confirming the tetramer dissociation mechanism.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.