# DBT JRF 2020 — Question 126

Exam: DBT JRF 2020 · Section: B · Topic: Biochemistry · Difficulty: Medium

## Question

The genetic disease familial Hypercholesterolemia that leads to an increase in blood cholesterol is caused due to

## Options

- **A.** increased hydrolysis of stored intracellular cholesteryl esters
- **B.** mutation in the low-density lipoprotein (LDL) receptor
- **C.** increased de novo cholesterol synthesis
- **D.** consuming cholesterol rich foods

## Answer

Option B

## Explanation

Familial Hypercholesterolaemia (FH): an autosomal dominant disorder of lipoprotein metabolism. Molecular basis: Loss-of-function mutations in the LDLR gene (LDL receptor, chromosome 19p13.2). Normal function: LDLR on hepatocytes and peripheral cells binds ApoB-100 on LDL particles → receptor-mediated endocytosis → LDL taken into cell → cholesterol released for cellular use → LDLR recycled to surface; excess intracellular cholesterol suppresses HMG-CoA reductase (reduces de novo synthesis) and downregulates LDLR expression. In FH: defective LDLR → LDL cannot be cleared from blood → plasma LDL-cholesterol dramatically elevated (>7 mmol/L in heterozygotes; >13 mmol/L in homozygotes) → premature atherosclerotic cardiovascular disease (ASCVD). PCSK9 is a regulatory protease that degrades LDLRs — anti-PCSK9 antibodies are now used therapeutically.

Source: https://mypyqbuddy.com/questions/the-genetic-disease-familial-hypercholesterolemia-that-leads-to-6a05a8a02adafec470293296