Familial hypercholesterolemia (FH) is caused by LDL receptor mutations. Which category of LDL receptor mutation results in the most severe phenotype (homozygous FH with cholesterol >600 mg/dL)?

• A Class IV mutations causing defective LDL binding due to mutations in the ligand-binding domain
• B Class I mutations causing failure of receptor synthesis in the endoplasmic reticulum ✓
• C Class V mutations causing defective receptor recycling (receptor is not released from endosome and is degraded instead of recycled)
• D Class II mutations causing transport arrest in the ER/Golgi, preventing receptor delivery to the cell surface

Explanation

LDL receptor mutations are classified into 5 classes. Class I mutations (null alleles) completely abolish receptor synthesis; no functional receptor is produced. These cause the most severe FH because there is zero LDL clearance. Class II mutations (transport defective) are the most common in clinical FH. Class IV (defective LDL binding) and Class V (recycling defective) produce partial functional impairment. Homozygous Class I null mutations result in total absence of LDL receptor function, causing extremely high LDL cholesterol (>600 mg/dL) with childhood xanthomas and premature CAD.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

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