The most common genetic defects in<unk>  are LDLR mutations (prevalence 1 in 250, depending on the population), ApoB mutations (prevalence 1 in 1000), PCSK9 mutations (less than 1 in 2500) and LDLRAP1. The related disease sitosterolemia, which has many similarities with<unk>  and also features cholesterol accumulation in tissues, is due to ABCG5 and ABCG8 mutations. LDL receptor LDLR pathway Schematic representation of the LDL receptor protein. The LDL receptor gene is located on the short arm of chromosome 19 (19p13.1-13.3). It comprises 18 exons and spans 45 kb, and the protein gene product contains 839 amino acids in mature form. A single abnormal copy (heterozygote) of<unk>  causes cardiovascular disease by the age of 50 in about 40% of cases. Having two abnormal copies (homozygote) causes accelerated atherosclerosis in childhood, including its complications. The plasma LDL levels are inversely related to the activity of LDL receptor (LDLR). Homozygotes have LDLR activity of less than 2%, while heterozygotes have defective LDL processing with receptor activity being 2–25%, depending on the nature of the mutation. Over 1000 different mutations are known. There are five major classes of<unk>  due to LDLR mutations: *Class I: LDLR is not synthesized at all. *Class II: LDLR is not properly transported from the endoplasmic reticulum to the Golgi apparatus for expression on the cell surface. *Class III: LDLR does not properly bind LDL on the cell surface because of a defect in either apolipoprotein B100 (R3500Q) or in LDL-R. *Class IV: LDLR bound to LDL does not properly cluster in clathrin-coated pits for receptor-mediated endocytosis (pathway step 2). *Class V: LDLR is not recycled back to the cell surface (pathway step 5). Apolipoprotein B Apolipoprotein B, in its ApoB100 form, is the main apolipoprotein, or protein part of the lipoprotein particle. Its gene is located on the second chromosome (2p24-p23) and is 46.2 kb long.<unk>  is often associated with the mutation of R3500Q, which causes replacement of arginine by glutamine at position 3500. The mutation is located on a part of the protein that normally binds with the LDL receptor, and binding is reduced as a result of the mutation. Like LDLR, the number of abnormal copies determines the severity of the<unk> . PCSK9 Mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene were linked to autosomal dominant (i.e. requiring only one abnormal copy)<unk>  in a 2003 report. The gene is located on the first chromosome (1p34.1-p32) and encodes a 666 amino acid protein that is expressed in the liver. It has been suggested that PCSK9 causes<unk>  mainly by reducing the number of LDL receptors on liver cells. LDLRAP1 Abnormalities in the ARH gene, also known as LDLRAP1, were first reported in a family in 1973. In contrast to the other causes, two abnormal copies of the gene are required for<unk>  to develop (autosomal recessive). The mutations in the protein tend to cause the production of a shortened protein. Its real function is unclear, but it seems to play a role in the relation between the LDL receptor and clathrin-coated pits. People with autosomal recessive<unk>  tend to have more severe disease than LDLR-heterozygotes but less severe than LDLR-homozygotes.
Familial hypercholesterolemia
Familial hypertriglyceridemia
Combined hyperlipidemia
Apolipoprotein B deficiency
Familial multiple lipomatosis
Marfanoid
Fruitarianism
Fabry disease