A 35-year-old man with tendon xanthomas, corneal arcus, and premature coronary artery disease has LDL-cholesterol of 580 mg/dL. His father died of MI at age 42. The most likely molecular defect is:
- A Defective apolipoprotein CII
- B Gain-of-function mutation in PCSK9
- C Loss-of-function mutation in the LDL receptor gene ✓
- D Lipoprotein lipase deficiency
Correct answer: C. Loss-of-function mutation in the LDL receptor gene
Explanation
Familial hypercholesterolemia (FH) is most commonly caused by loss-of-function mutations in the LDL receptor (LDLR) gene. Heterozygotes have LDL-C ~270–500 mg/dL; homozygotes exceed 800 mg/dL. Tendon xanthomas and early coronary disease are hallmarks. PCSK9 gain-of-function also causes FH but is far less common. ApoC-II deficiency causes hypertriglyceridemia (type I hyperlipoproteinemia). LPL deficiency causes chylomicronemia.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.