Familial HDL deficiency is a condition characterized by low levels of high-density lipoprotei% (HDL) in the blood. HDL is a molecule that transports cholesterol and certain fats called phospholipids through the bloodstream from the body's tissues to the liver. Once in the liver, cholesterol and phospholipids are redistributed to other tissues or removed from the body. HDL is often referred to as "good cholesterol" because high levels of this substance reduce the chances of developing heart and blood vessel (cardiovascular) disease. People with familial HDL deficiency may develop cardiovascular disease at a relatively young age, often before age 50.

Severely reduced levels of HDL in the blood is a characteristic feature of a related disorder called Tangier disease. People with Tangier disease have additional signs and symptoms, such as disturbances in nerve function; enlarged, orange-colored tonsils; and clouding of the clear covering of the eye (corneal clouding). However, people with familial HDL deficiency do not have these additional features.

Mutations in the ABCA1 gene or the APOA1 gene cause familial HDL deficiency. The proteins produced from these genes work together to remove cholesterol and phospholipids from cells.

The ABCA1 gene provides instructions for making a protein that removes cholesterol and phospholipids from cells by moving them across the cell membrane. The movement of these substances across the membrane is enhanced by another protein called apolipoprotein A-I (apoA-I), which is produced by the APOA1 gene. Once outside the cell, the cholesterol and phospholipids combine with apoA-I to form HDL. ApoA-I also triggers a reaction that converts cholesterol to a form that can be fully integrated into HDL and transported through the bloodstream.

ABCA1 gene mutations and some APOA1 gene mutations prevent the release of cholesterol and phospholipids from cells. Other mutations in the APOA1 gene reduce the protein's ability to stimulate the conversion of cholesterol. These ABCA1 and APOA1 gene mutations decrease the amount of cholesterol or phospholipids available to form HDL, resulting in low levels of HDL in the blood. A shortage (deficiency) of HDL is believed to increase the risk of cardiovascular disease.

Normal Function

The ABCA1 gene belongs to a group of genes called the ATP-binding cassette family. These genes provide instructions for making proteins that transport molecules across cell membranes. The ABCA1 protein is produced in many tissues, but high levels of this protein are found in the liver and in immune cells called macrophages.

The ABCA1 protein helps move cholesterol and certain fats called phospholipids across the cell membrane to the outside of the cell. These substances are then picked up by a protein called apolipoprotein A-I (apoA-I), which is produced from the APOA1 gene. ApoA-I, cholesterol, and phospholipids combine to make high-density lipoprotein (HDL), often referred to as "good cholesterol" because high levels of this substance reduce the chances of developing heart and blood vessel (cardiovascular) disease.

HDL carries cholesterol and phospholipids through the bloodstream from the body's tissues to the liver. Once in the liver, cholesterol and phospholipids are redistributed to other tissues or removed from the body. The process of removing excess cholesterol from cells is extremely important for balancing cholesterol levels and maintaining cardiovascular health.

Health Conditions Related to Genetic Changes

Familial HDL deficiency

Variants (also called mutations) in the ABCA1 gene can cause a condition called familial HDL deficiency. People with this condition have reduced levels of HDL in their blood and may experience early-onset cardiovascular disease, often before age 50. While one copy of the altered ABCA1 gene causes familial HDL deficiency, two copies of the altered gene cause a more severe disorder called Tangier disease (described below).

Most ABCA1 gene variants that cause familial HDL deficiency change single protein building blocks (amino acids) in the ABCA1 protein. Other variants alter the protein in other ways. The changes in the ABCA1 protein prevent the release of cholesterol and phospholipids from cells, decreasing the amount of these substances available to form HDL. As a result, the levels of HDL in the blood are low. A shortage (deficiency) of HDL is believed to increase a person's risk of cardiovascular disease.

Tangier disease

Several variants in the ABCA1 gene have been found to cause Tangier disease. Most of these variants change single amino acids in the ABCA1 protein. These variants prevent the release of cholesterol and phospholipids from cells. As a result, these substances accumulate within cells, causing certain body tissues to enlarge and the tonsils to acquire a yellowish-orange color. A buildup of cholesterol can be toxic to cells, leading to impaired cell function or cell death. In addition, the inability to transport cholesterol and phospholipids out of cells results in very low HDL levels, which may increase the risk of cardiovascular disease. All these factors cause the signs and symptoms of Tangier disease.

Other Names for This Gene

• ABC1
• ABCA1_HUMAN
• ATP binding cassette transporter 1
• ATP-binding cassette 1
• ATP-binding cassette, sub-family A (ABC1), member 1
• CERP
• cholesterol efflux regulatory protein
• FLJ14958
• HDLDT1
• high density lipoprotein deficiency, Tangier type, 1
• TGD

Genomic Location

Normal Function

The APOA1 gene provides instructions for making a protein called apolipoprotein A-I (apoA-I). ApoA-I is a component of high-density lipoprotein (HDL). HDL is a molecule that transports cholesterol and certain fats called phospholipids through the bloodstream from the body's tissues to the liver. Once in the liver, cholesterol and phospholipids are redistributed to other tissues or removed from the body.

ApoA-I attaches to cell membranes and promotes the movement of cholesterol and phospholipids from inside the cell to the outer surface. Once outside the cell, these substances combine with apoA-I to form HDL. ApoA-I also triggers a reaction called cholesterol esterification that converts cholesterol to a form that can be fully integrated into HDL and transported through the bloodstream.

HDL is often referred to as "good cholesterol" because high levels of this substance reduce the chances of developing heart and blood vessel (cardiovascular) disease. The process of removing excess cholesterol from cells is extremely important for balancing cholesterol levels and maintaining cardiovascular health.

Health Conditions Related to Genetic Changes

Familial HDL deficiency

Mutations in the APOA1 gene cause familial HDL deficiency, an inherited condition characterized by low levels of HDL in the blood and an elevated risk for early-onset cardiovascular disease, which often occurs before age 50. These mutations lead to an altered apoA-I protein. Some versions of the altered protein are less able to promote the removal of cholesterol and phospholipids from cells, which decreases the amount of these substances available to form HDL. Other versions of the altered protein are less able to stimulate cholesterol esterification, which means cholesterol cannot be integrated into HDL particles. Both types of mutation result in low HDL levels. A shortage (deficiency) of HDL is believed to increase the risk of cardiovascular disease.

Other disorders

Mutations in the APOA1 gene can also cause a condition called familial visceral amyloidosis, which is characterized by an abnormal accumulation of proteins (amyloidosis) in internal organs (viscera). The mutations that cause this condition alter the apoA-I protein. Abnormal apoA-I proteins stick together to form amyloid deposits that impair the function of the affected organs. The liver, kidneys, and heart are commonly affected by amyloidosis. Depending on the organs involved, the signs and symptoms of the condition vary. Affected individuals can have an enlarged liver (hepatomegaly), chronic kidney disease, or a form of heart disease called cardiomyopathy. However, in some people, the condition is very mild and causes no apparent signs or symptoms.

Other Names for This Gene

• apo-AI
• apoA-I
• APOA1_HUMAN
• apolipoprotein A-I

Genomic Location

Familial HDL deficiency is inherited in an autosomal dominant pattern, which means an alteration in one copy of either the ABCA1 or the APOA1 gene in each cell is sufficient to cause the disorder. People with alterations in both copies of the ABCA1 gene develop the related disorder Tangier disease.