**Question:** Tangier disease is due to deficiency of which enzyme?

**Core Concept:** Tangier disease is a rare autosomal recessive disorder characterized by very low levels of high-density lipoprotein (HDL) cholesterol. HDL cholesterol plays a crucial role in maintaining cardiovascular health by removing cholesterol from peripheral tissues and transporting it back to the liver for excretion.

**Why the Correct Answer is Right:** Tangier disease results from a deficiency of the ATP-binding cassette transporter A1 (ABCA1). ABCA1 is a membrane protein encoded by the ABCA1 gene, which facilitates the cellular cholesterol efflux to apolipoprotein A1 (apoA1) and phospholipids, leading to the formation of pre-beta high-density lipoprotein particles. In the absence or deficiency of ABCA1, cholesterol cannot be effluxed from cells, resulting in decreased HDL cholesterol levels and the characteristic clinical features of Tangier disease.

**Why Each Wrong Option is Incorrect:**

A. **Lack of cholesteryl ester transport protein (CETP):** Tangier disease is not due to a deficiency of CETP, which is an enzyme that facilitates the exchange of cholesteryl esters between HDL and triglyceride-rich lipoproteins.

B. **Lack of lecithin:cholesterol acyltransferase (LCAT):** Tangier disease is not due to a deficiency of LCAT, an enzyme that catalyzes the formation of cholesteryl ester-rich HDL particles from phospholipid-rich pre-beta HDL particles.

C. **Lack of lipoprotein lipase (LPL):** Tangier disease is not due to a deficiency of LPL, an enzyme that hydrolyzes triglycerides in chylomicrons, very low-density lipoproteins (VLDL), intermediate-density lipoproteins (IDL), and low-density lipoproteins (LDL).

D. **Lack of apolipoprotein A1:** Tangier disease is not due to a deficiency of apolipoprotein A1 (apoA1), a protein that binds to HDL particles and promotes cholesterol efflux from cells.

**Clinical Pearl:** Tangier disease is a rare genetic disorder that should be considered in the differential diagnosis of patients presenting with low HDL cholesterol levels and increased triglyceride levels, especially in the context of premature atherosclerosis.

**Correct Answer:** D. **Lack of apolipoprotein A1:** Tangier disease is due to a genetic mutation in the ABCA1 gene, which encodes the ABCA1 protein. This deficiency results in impaired cholesterol efflux from cells, leading to low HDL cholesterol levels and increased triglyceride levels. The ABCA1 protein is essential for the formation of cholesterol-poor high-density lipoprotein (HDL) particles, which are crucial for reverse cholesterol transport, the process by which excess cholesterol is transported from peripheral tissues to the liver for excretion.

**Why the Other Options are Incorrect:**

A. Lack of apolipoprotein A1 (apoA1) is the correct answer because ABCA1 deficiency directly affects the ABCA