Mutations involving single genes follow one of three patterns of inheritance: autosomal dominant, autosomal recessive, or X-linked. Autosomal Dominant Inheritance Familial hypercholesterolemia Huntington disease Marfan syndrome Ehlers-Danlos syndrome Hereditary spherocytosis Neurofibromatosis, type 1 Adult polycystic kidney disease Familial Hypercholesterolemia Familial hypercholesterolemia is among the most common mendelian disorders; the frequency of the heterozygous condition is 1 in 500 in the general population. It is caused by a mutation in the LDLR gene that encodes the receptor for low-density lipoprotein (LDL), the form in which 70% of total plasma cholesterol is transpoed. A brief review of the synthesis and transpo of cholesterol follows. Normal Cholesterol Metabolism. Cholesterol may be derived from the diet or from endogenous synthesis. Dietary triglycerides and cholesterol are incorporated into chylomicrons in the intestinal mucosa, which drain by way of the gut lymphatics into the blood. These chylomicrons are hydrolyzed by an endothelial lipoprotein lipase in the capillaries of muscle and fat. The chylomicron remnants, rich in cholesterol, are then delivered to the liver. Some of the cholesterol enters the metabolic pool (to be described), and some is excreted as free cholesterol or bile acids into the biliary tract. The endogenous synthesis of cholesterol and LDL begins in the liver (Fig. 6-2). The first step in the synthesis of LDL is the secretion of triglyceride-rich very- low-density lipoprotein (VLDL) by the liver into the blood. In the capillaries of adipose tissue and muscle, the VLDL paicle undergoes lipolysis and is conveed to intermediate- density lipoprotein (IDL). In comparison with VLDL, the content of triglyceride is reduced and that of cholesteryl esters enriched in intermediate-density lipoprotein (IDL), but IDL retains on its surface two of the three VLDL- associated apolipoproteins B-100 and E. Fuher metabo- lism of IDL occurs along two pathways: Most of the IDL paicles are directly taken up by the liver through the LDL receptor described later; others are conveed to cholesterol- rich LDL by a fuher loss of triglycerides and apolipopro- tein E. In the liver cells, IDL is recycled to generate VLDL. Two thirds of the resultant LDL paicles are metabo- lized by the LDL receptor pathway, and the rest is metabo- lized by a receptor for oxidized LDL (scavenger receptor), to be described later. The LDL receptor binds to apolipo- proteins B-100 and E and thus is involved in the transpo of both LDL and IDL. Although the LDL receptors are widely distributed, approximately 75% are located on hepatocytes, so the liver plays an extremely impoant role in LDL metabolism. The first step in the receptor-mediated transpo of LDL involves binding to the cell surface receptor, followed by endocy- totic internalization inside so-called "clathrin-coated pits" (Fig. 6-3). Within the cell, the endocytic vesicles fuse with the lysosomes, and the LDL molecule is enzymatically degraded, resulting ultimately in the release of free cholesterol into the cytoplasm. The cholesterol not only is used by the cell for membrane synthesis but also takes pa in intracel- lular cholesterol homeostasis by a sophisticated system of feed- back control: * It suppresses cholesterol synthesis by inhibiting the activity of the enzyme 3-hydroxy-3-methylglutaryl- coenzyme A reductase (HMG-CoA reductase), which is the rate-limiting enzyme in the synthetic pathway. * It stimulates the formation of cholesterol esters for storage of excess cholesterol. * It downregulates the synthesis of cell surface LDL recep- tors, thus protecting cells from excessive accumulation of cholesterol. The transpo of LDL by the scavenger receptors, alluded to earlier, seems to take place in cells of the mononuclear- phagocyte system and possibly in other cells as well. Monocytes and macrophages have receptors for chemically modified (e.g., acetylated or oxidized) LDLs. The amount catabolized by this "scavenger receptor" pathway is directly related to the plasma cholesterol level. (Robbins Basic Pathology,9th edition,pg no. 219)