Familial hypercholesterolemia (FH) is caused by LDL receptor mutations. In compound heterozygous FH with two different LDL receptor mutations, a Western blot of patient fibroblasts shows LDL receptors of normal size but their surface expression is severely reduced. The mutation MOST likely affects:
- A The ligand-binding domain (class I mutation — no receptor protein made)
- B The receptor's ER-to-Golgi transport signal (class II mutation — receptor accumulates in ER, not trafficked to surface) ✓
- C The transmembrane domain causing receptor aggregation on the cell surface
- D The cytoplasmic tail NPxY motif required for coated pit clustering (class IV mutation)
Explanation
LDLR mutations are classified: Class I = no protein made; Class II = protein made but misfolded and trapped in ER/Golgi (most common); Class III = protein reaches cell surface but cannot bind LDL; Class IV = protein reaches surface and binds LDL but cannot cluster in clathrin-coated pits (NPxY motif); Class V = protein internalised but cannot recycle back to surface. Normal-sized receptor on Western blot but absent from surface implies Class II (trafficking defect) — receptor is synthesized and detected on blot but cannot exit the ER due to misfolding that prevents COPII vesicle incorporation.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.