Familial hypercholesterolemia is one of a group of metabolic disorders called the hyperlipoproteinemias. These diseases are characterized by elevated levels of plasma lipids (cholesterol, triglycerides, or both) carried by apo lipoprotein B (apoB)–containing lipoproteins. Other monogenic hyperlipoproteinemias, each with distinct biochemical and clinical phenotypes, have also been recognized.

In addition to variants in the LDL receptor gene (Table 1), abnormalities in three other genes can lead to familial hypercholesterolemia (Fig. 1). Remarkably, all four of the genes associated with familial hypercholesterolemia disrupt the function or abundance either of the LDL receptor at the cell surface or of apoB, the major protein component of LDL and a ligand for the LDL receptor. Because of its importance, we first review familial hypercholesterolemia due to pathogenic variants in the LDL receptor. We also discuss variants in the PCSK9 protease gene; although gain-of-function variants in this gene cause hypercholesterolemia, the greater importance of PCSK9 lies in the fact that several common loss-of-function sequence variants lower plasma LDL cholesterol levels, conferring substantial protection from coronary heart disease.

Table1. Four Genes Associated With Familial Hypercholesterolemia

Fig1. The four proteins associated with familial hypercholesterolemia. The low-density lipoprotein (LDL) receptor binds apoprotein B-100. Pathogenic variants in the LDL receptor-binding domain of apoprotein B-100 impair LDL binding to its receptor, reducing the removal of LDL cholesterol from the circulation. Clustering of the LDL receptor–apoprotein B-100 complex in clathrin coated pits requires the ARH adaptor protein, which links the receptor to the endocytic machinery of the coated pit. Homozygous variants in the ARH protein impair the internalization of the LDL:LDL receptor complex, thereby impairing LDL clearance. PCSK9 protease activity targets LDL receptors for lysosomal degradation, preventing them from recycling back to the plasma membrane (see text).

Familial Hypercholesterolemia Due to Pathogenic Variants in the LDL Receptor

Pathogenic variants in the LDL receptor gene (LDLR) are the most common cause of familial hypercholesterolemia (Case 16). The receptor is a cell surface protein responsible for binding LDL and delivering it to the cell interior. Elevated plasma concentrations of LDL cholesterol lead to premature atherosclerosis (accumulation of cholesterol by macrophages in the subendothelial space of major arteries) and increased risk for heart attack and stroke in both untreated heterozygote and homozygote carriers of mutant alleles. Physical stigmata of familial hypercholesterolemia include xanthomas (cholesterol deposits in skin and tendons) and premature arcus corneae (deposits of cholesterol around the periphery of the cornea). Few diseases have been as thoroughly characterized; the sequence of pathologic events from the affected locus to its effect on individuals and populations has been meticulously documented.

Genetics. Familial hypercholesterolemia due to pathogenic variants in the LDLR gene is inherited as an autosomal semidominant trait. Both homozygous and heterozygous phenotypes are known, and a clear gene dosage effect is evident; the disease manifests earlier and much more severely in homozygotes than in hetero zygotes, reflecting the greater reduction in the number of LDL receptors and the greater elevation in plasma LDL cholesterol (Fig. 2). Homozygotes may have clinically significant coronary artery disease in child hood and, if untreated, few live beyond the third decade. The heterozygous form of the disease, with a population frequency of ~2 per 1000, is one of the most common single-gene disorders. Heterozygotes have levels of plasma cholesterol that are approximately twice those of controls (see Fig.2). Because of the inherited nature of familial hypercholesterolemia, it is important to make the diagnosis in the ~5% of survivors of premature ( <50 years of age) myocardial infarction who are heterozygotes for an LDL receptor defect. It is important to stress, however, that among those in the general population with plasma cholesterol concentrations above the 95th percentile for age and sex, only ~1 in 20 has familial hypercholesterolemia; most such individuals have an uncharacterized hypercholesterolemia due to multiple common genetic variants, as presented in Chapter 9.

Fig2. Gene dosage in low-density lipoprotein (LDL) deficiency. Shown is the distribution of total plasma cholesterol levels in 49 patients homozygous for deficiency of the LDL receptor, their parents (obligate heterozygotes), and normal controls. (Redrawn from Goldstein Jl, Brown MS: Familial hypercholesterolemia. In Scriver CR, Beaudet Al, Sly WS, et al, editors: The metabolic bases of inherited disease, ed 6, New York, 1989, McGraw-Hill, pp 1215–1250.)

Cholesterol Uptake by the LDL Receptor. Normal cells obtain cholesterol from either de novo synthesis or the uptake from plasma of exogenous cholesterol bound to lipoproteins, especially LDL. The majority of LDL uptake is mediated by the LDL receptor, which recognizes apoprotein B-100, the protein moiety of LDL. LDL receptors on the cell surface are localized to invaginations (coated pits) lined by the protein clathrin (Fig. 3). Receptor-bound LDL is brought into the cell by endocytosis of the coated pits, which ultimately evolve into lysosomes in which LDL is hydrolyzed to release free cholesterol. The increase in free intracellular cholesterol reduces endogenous cholesterol formation by suppressing the rate-limiting enzyme of the synthetic pathway, 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase. Cholesterol not required for cellular metabolism or membrane synthesis may be reesterified for storage as cholesteryl esters, a process stimulated by the activation of acyl-coenzyme A:cholesterol acyltransferase (ACAT). The increase in intracellular cholesterol also reduces synthesis of the LDL receptor (see Fig. 3).

Fig3. The cell biology and biochemical role of the low-density lipoprotein (LDL) receptor and the six classes of variants that alter its function. After synthesis in the endoplasmic reticulum (ER), the receptor is transported to the Golgi apparatus and subsequently to the cell surface. Normal receptors are localized to clathrin-coated pits, which invaginate, creating coated vesicles and then endosomes, the precursors of lysosomes. Normally, intracellular accumulation of free cholesterol is prevented because the increase in free cholesterol (A) decreases the formation of LDL receptors, (B) reduces de novo cholesterol synthesis, and (C) increases the storage of cholesteryl esters. The biochemical phenotype of each class of mutant is discussed in the text. ACAT, Acyl-coenzyme A:cholesterol acyltransferase; HMG CoA reductase, 3-hydroxy-3-methylglutaryl coenzyme A reductase. (Modified from Brown MS, Goldstein Jl: The LDL receptor and HMG-CoA reductase – Two membrane molecules that regulate cholesterol homeostasis, Curr Top Cell Regul 26:3–15, 1985.)

Classes of Variants in the LDL Receptor

 More than 1100 different variants have been identified in the LDLR gene, and these are distributed throughout the gene and protein sequence. Not all of the reported changes are functionally significant, and some disturb receptor function more severely than others. The great majority of alleles are single nucleotide substitutions, small insertions, or deletions; structural rearrangements account for only 2% to 10% of the LDLR alleles in most populations. The mature LDL receptor has five dis tinct structural domains that for the most part have distinguishable functions that mediate the steps in the life cycle of an LDL receptor, shown in Fig. 3. Analysis of the effect on the receptor of variants in each domain has played an important role in defining the function of each domain. These studies exemplify the important contribution that genetic analysis can make in determining the structure-function relationships of a protein.

Fibroblasts cultured from affected patients have been used to characterize the mutant receptors and the resulting disturbances in cellular cholesterol metabolism. LDLR variants can be grouped into six classes, depending on which step of the normal cellular itinerary of the receptor is disrupted by the variant (see Fig. 3).

• Class 1 variants are null alleles that prevent the syn thesis of any detectable receptor; they are the most common type of disease-causing variants at this locus. In the remaining five classes, the receptor is synthesized normally, but its function is impaired.

• Class 2 variants (like those in classes 4 and 6) define features of the polypeptide critical to its subcellular localization. The relatively common class 2 variants are designated transport deficient because the LDL receptors accumulate at the site of their synthesis, the ER, instead of being transported to the Golgi com plex. These alleles are predicted to prevent proper folding of the protein, an apparent requisite for exit from the ER.

• Class 3 variant receptors reach the cell surface but are incapable of binding LDL.

 • Class 4 variants impair localization of the receptor to the coated pit, and consequently the bound LDL is not internalized. These variants alter or remove the cytoplasmic domain at the carboxyl terminus of the receptor, demonstrating that this region normally tar gets the receptor to the coated pit.

• Class 5 variants are recycling-defective alleles. Receptor recycling requires the dissociation of the receptor and the bound LDL in the endosome. Variants in the epidermal growth factor precursor homology domain prevent the release of the LDL ligand. This failure leads to degradation of the receptor, presumably because an occupied receptor cannot return to the cell surface.

 • Class 6 variants lead to defective targeting of the mutant receptor to the basolateral membrane, a process that depends on a sorting signal in the cytoplasmic domain of the receptor. Variants affecting the signal can mistarget the mutant receptor to the apical surface of hepatic cells, thereby impairing the recycling of the receptor to the basolateral membrane and leading to an overall reduction of endocytosis of the LDL receptor.

The PCSK9 Protease, a Drug Target for Lowering LDL Cholesterol

 Rare cases of autosomal dominant familial hypercholesterolemia have been found to result from gain-of-function missense variants in the gene encoding PCSK9 protease (proprotein convertase subtilisin/kexin type 9). The role of PCSK9 is to target the LDL receptor for lysosomal degradation, thereby reducing receptor abundance at the cell surface (see Fig. 1). Consequently, the increase in PSCK9 activity associated with gain-of-function variants reduces the levels of the LDL receptor at the cell surface below normal, leading to increased blood levels of LDL cholesterol and coronary heart disease.

Conversely, loss-of-function variants in the PCSK9 gene result in an increased number of LDL receptors at the cell surface by decreasing the activity of the protease. More receptors increase cellular uptake of LDL cholesterol, lowering cholesterol and providing protection against coronary artery disease. Notably, the complete absence of PCSK9 activity in the few known individuals with two PCSK9 null alleles appears to have no adverse clinical consequences.

Some PCSK9 Sequence Variants Protect Against Coronary Heart Disease. The link between monogenic familial hypercholesterolemia and the PCSK9 gene suggested that common sequence variants in PCSK9 might be linked to very high or very low LDL cholesterol levels in the general population. Importantly, several PCSK9 sequence variants are strongly linked to low levels of plasma LDL cholesterol (Table2). For example, a study that used US census definitions showed that in the Black population one of two PCSK9 nonsense variants is found in 2.6% of all subjects; each variant is associated with a mean reduction in LDL cholesterol of ~40%. This reduction in LDL cholesterol has a powerful protective effect against coronary artery disease, reducing the risk by ~90%; only ~1% of Black sub jects carrying one of these two PCSK9 nonsense variants developed coronary artery disease over a 15-year period, compared to almost 10% of individuals without either variant. A missense allele (p.Arg46leu) is more common in white US census category populations (3.2% of subjects) but appears to confer only a ~50% reduction in coronary heart disease. These findings have major public health implications because they suggest that modest but lifelong reductions in plasma LDL cholesterol levels of 20 to 40 mg/dl would significantly decrease the incidence of coronary heart disease in the population. The strong protective effect of PCSK9 loss of-function alleles, together with the apparent absence of any clinical sequelae in subjects with a total absence of PCSK9 activity, made PCSK9 a strong candidate target for drugs that inactivate or diminish the activity of the enzyme.

Table2. PCSK9 Variants Associated With Low LDL Cholesterol Levels

Finally, these discoveries emphasize how the investigation of rare genetic disorders can lead to important new knowledge about the genetic contribution to common genetically complex diseases.

Clinical Implications of the Genetics of Familial Hypercholesterolemia. Early diagnosis of the familial hypercholesterolemias is essential both to permit the prompt application of cholesterol-lowering therapies to prevent coronary artery disease and to initiate genetic screening of first-degree relatives. With appropriate drug therapy, familial hypercholesterolemia heterozygotes have a normal life expectancy. For homozygotes, onset of coronary artery disease can be remarkably delayed by plasma apheresis (which removes the hypercholesterolemic plasma) but will ultimately require liver transplantation.

Finally, the elucidation of the biochemical basis of familial hypercholesterolemia has had a profound impact on the treatment of the vastly more common forms of sporadic hypercholesterolemia by leading to the development of the statin class of drugs that inhibit de novo cholesterol biosynthesis. Newer therapies include monoclonal antibodies that directly target PCSK9 and lower LDL cholesterol by an additional 60% in clinical trials, prompting approval and use around the world.

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