Hypercholesterolemia (Hypercholesterolemia) - Genes LDLR, APOB, LDLRAP1, and PCSK9.
Hypercholesterolemia is an alteration of cholesterol metabolism, characterized by very high concentrations of blood cholesterol. As excess cholesterol circulates in the bloodstream, it accumulates in various tissues, facilitating the development of premature coronary heart disease, arteriosclerosis and tendon xanthomas.
In general, this process is due to a combination of genetic and environmental factors. On the one hand, mutations in the LDLR, APOB, LDLRAP1 and PCSK9 genes lead to hypercholesterolemia. On the other hand, environmental factors such as diet, exercise and consumption of snuff influence blood cholesterol levels. The most common cause of high cholesterol is due to mutations in the LDLR gene.
The LDLR gene, located on the short arm of chromosome 19 (19p13.2), encoding the LDL receptor (LDLR). This receptor binds to low density lipoprotein (LDL), which are the main carriers of cholesterol in the blood. By removing low density lipoprotein from blood, these receptors play a critical role in regulating cholesterol concentrations, being particularly abundant in the liver. The number of lipoprotein receptors low density on the surface of liver cells determines the rate at which cholesterol (in the form of low density lipoprotein) is removed from the bloodstream. They have been identified over 1000 mutations in the LDLR gene that result in familial hypercholesterolemia. Some mutations in the LDLR gene reduce the number of receptors low density lipoprotein produced within cells. Other mutations alter the ability of receptors to remove low density lipoproteins from the bloodstream. As a result, individuals with mutations in the LDLR gene have very high concentrations of blood cholesterol.
The APOB gene located on the short arm of chromosome 2 (2p24-p23) encoding isoforms of apolipoprotein B, a short apolipoprotein form called B-48, and apolipoprotein long form called B-100 protein components of LDL particles that serve as ligands binding to its receptor LDLR. Apolipoprotein B-48, occurs in the intestine and is part of chylomicrons. These chylomicrons carry fat and cholesterol from the intestine into the circulation. Also they carry some vitamins (A and E). Apolipoprotein B-100 is produced in the liver and is one of the very low-density lipoprotein (VDDLs), intermediate density (IDAs) and low density (LDL). Low - density lipoproteins are the main carriers of cholesterol in blood. B-100 apolipoprotein, allowing these particles bind to specific receptors on the cell surface, mainly in the liver. Once attached to receptors, transport occurs within the cell where cleaved to release cholesterol is used, stored or removed from the body. They have been identified at least 5 APOB gene mutations in people with an inherited form of familial hypercholesterolemia called apolipoprotein B-100 defective (FDB). This alteration is characterized by very high levels of blood cholesterol and increased risk for developing heart disease. Each of these mutations change an amino acid in a critical region of apolipoprotein B-100. Altered protein prevents low density lipoproteins bind effectively to their receptors on the cell surface. As a result, fewer low density lipoproteins are removed from the blood, and cholesterol levels are much higher than normal. As excess cholesterol circulates in the bloodstream, it is deposited abnormally in tissues such as skin, tendons and coronary arteries. A buildup of cholesterol in the walls of coronary arteries greatly increases the risk of coronary obstruction.
The LDLRAP1 gene, located on the short arm of chromosome 1 (1p36.11), LDLRAP1 encoding protein which interacts with the receptor of low density lipoprotein. This protein receptors moves together with the attached low density lipoproteins from the cell surface into the cell, where cholesterol is released for use, stored or removed from the body. They have identified more than 10 mutations in the gene LDLRAP1 leading to a form of the autosomal recessive disease called hypercholesterolemia. These mutations lead to an abnormally small encoding nonfunctional version, protein or inhibit LDLRAP1 encoding this protein. Without LDLRAP1 protein receptor low - density lipoprotein they are not able to effectively remove low density lipoprotein blood. Although the receivers can still bind to low density lipoproteins, these molecules are not properly transported into cells, particularly in hepatocytes. As a result, they remain in the blood many very low-density lipoprotein. Because low density lipoproteins are the main carriers of cholesterol in the blood, individuals with mutations in the gene LDLRAP1 have very high concentrations of blood cholesterol. As excess cholesterol circulates in the bloodstream, it is deposited abnormally in tissues such as skin, tendons and coronary arteries. A buildup of cholesterol in the walls of coronary arteries greatly increases the risk of coronary obstruction.
The PCSK9 gene, located on the short arm of chromosome 1 (1p32.3), encoding proteins involved in degradation of the LDL receptor by binding, thereby regulating the receptors present on the cell surface and the LDL catabolism. It is, therefore, a protein that plays a very important role in cholesterol homeostasis. They have identified several mutations in the PCSK9 gene are involved in the development of familial hypercholesterolemia. These mutations change a single amino acid in the PCSK9 protein, which appears to increase the activity of PCSK9 protein or to a new function, atypical protein. PCSK9 overactive protein significantly reduces the number of lipoprotein receptors low density on the surface of hepatocytes. It is likely that the altered protein can cause these receptors to break down faster than normal. With fewer receptors to eliminate low - density lipoprotein blood, those affected have very high levels of blood cholesterol.
Most cases of hypercholesterolemia are not only a result of a hereditary condition, but are due to a combination of lifestyle and the effects of variations in many genes. Inherited forms of hypercholesterolemia due to mutations in the LDLR, APOB and PCSK9 genes have an autosomal dominant inheritance. Autosomal dominant inheritance means that a copy of an altered gene in each cell is sufficient to express the disease. An affected person usually inherit an altered copy of the gene from an affected parent and a normal copy of the gene from the other parent. Rarely, individuals with familial hypercholesterolemia are born with two mutated copies of the LDLR gene. This situation occurs when the affected person has two parents, each of whom spends an altered copy of the gene. The presence of two mutations of LDLR gene in a more intense form of hypercholesterolemia usually occurs in childhood. On the other hand, when hypercholesterolemia is due to mutations in the gene LDLRAP1, the disease is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.
Tests in IVAMI: in IVAMI perform detection of mutations associated with hypercholesterolemia, by complete PCR amplification of the exons of the LDLR, APOB, LDLRAP1 and PCSK9 genes, respectively, and subsequent sequencing. We recommend starting by studying the LDLR gene by being in which mutations have been found more frequently, and continue to study other genes should not find mutations.
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).