Familial hypercholesterolemia, FH (type II hyperlipoproteinemia) is an autosomal dominant disorder that results from mutations affecting the structure and function of the cell-surface receptor that binds plasma LDLs (low density lipoproteins) removing them from the circulation. The defects in LDL-receptor (LDLR) interaction result in lifelong elevation of LDL-cholesterol in the blood. The resultant hypercholesterolemia leads to premature coronary artery disease and atherosclerotic plaque formation. FH was the first inherited disorder that was recognized as being a cause of myocardial infarction (heart attack).
Although the disease is inherited in an autosomal dominant manner, the disease exhibits a gene dosage effect. Homozygous individuals are more severely affected than are heterozygotes. Heterozygotes for FH occur with a frequency of 1 in 500 which makes this disease one of the most common inherited disorders in metabolism. The LDLR gene is located on chromosome 19p13.2 spanning 45 kilobases (kb) and is composed of 18 exons that generate five alternatively spliced mRNAs.These five mRNAs encode LDLR isoforms identified as isoform 1 (860 amino acids), 2 (858 amino acids), 3 (819 amino acids), 4 (692 amino acids), and 6 (682 amino acids).
Five different classes of receptor mutation have been identified in FH with each class having multiple alleles. More than 700 different mutations in the LDLR gene have been found in FH (see UMD-LDLR Database page for listings). The class 1 mutations are null mutations because these result in a failure to make any detectable LDLR protein. Class 2 mutations are the most common and represent intracellular transport defects. The LDLR does not move between the endoplasmic reticulum (ER) and the Golgi membranes. Class 3 mutations represent LDLRs that are delivered to the cell surface but fail in their ability to bind LDL. Class 4 mutations are the rarest and result in LDLR protein that will bind LDL but the LDLR-LDL complexes cannot be internalized. Class 5 mutations result in receptors that bind and internalize the LDL particle but cannot release the particles in the endosomes so the receptors cannot recycle back to the cell surface.
The clinical characteristics of FH include elevated concentrations of plasma LDL and deposition of LDL-cholesterol in the arteries, tendons and skin. Fat deposits in the arteries are called atheromas and in the skin and tendons they are called xanthomas. In heterozygotes, hypercholesterolemia is the earliest clinical manifestation in FH and remains the only clinical finding during the first decade of life. Xanthomas and the characteristic arcus cornea (whitish ring on the peripheral cornea) begin to appear in the second decade. The symptoms of coronary heart disease present in the fourth decade. At the time of death 80% of heterozygotes will have xanthomas. The clinical picture is more uniform and severe in homozygotes. Homozygotes present with marked hypercholesterolemia at birth and it will persist throughout life. Xanthomas, arcus cornea and atherosclerosis will develop during childhood in homozygotes. Death from myocardial infarction usually will occur before the age of 30 in homozygotes. Shown in the Table below are representative values of various plasma lipids in normal, heterozygote FH and homozygote FH individuals. These values are not intended to be used as diagnostic and can vary greatly in certain individuals from those given here.
|Genotype||Age, yrs||Total Cholesterol (mg/dl)||LDL (mg/dl)||HDL (mg/dl)||Triglycerides (mg/dl)|
|Normal||1-19||175 ± 30||110 ± 25||55 ± 15||60 ± 25|
|Heterozygotes||1-19||300 ± 60||240 ± 60||45 ± 10||80 ± 50|
|Homozygotes||1-19||680 ± 170||625 ± 160||35 ± 10||100 ± 50|
|Normal||>20||200 ± 40||125 ± 30||55 ± 15||80 ± 30|
|Heterozygotes||>20||380 ± 80||300 ± 80||45 ± 15||150 ± 75|
As indicated above there have been over 700 different mutations identified in FH patients. Of diagnostic significance is the fact that 45 different polymorphisms in the LDLR gene have been identified and can be detected using RFLP and/or SSCP techniques.
Class 1 Mutations: Multiple molecular mechanisms have been shown to result in the null mutations that comprise the class 1 FH family. The alterations include deletions that eliminate the LDLR gene promoter. In addition, frameshift, nonsense and splicing mutations cause the null phenotype.
Class 2 Mutations: There are two subclasses of class 2 mutations in FH. Class 2A mutations result in an LDLR protein that fails to be transported out of the ER. Class 2B mutations are "leaky" in that some of the newly synthesized LDLR protein is transported to the Golgi but at a reduced rate compared to wild-type. The class 2B mutations are the more common type in this class of mutation. Most of the class 2 mutations are clustered in the exons that comprise the LDL-binding domain. The LDLR protein has a domain with homology to the epidermal growth factor (EGF) precursor protein (see the Growth Factors page) and most of the rest of the class 2 mutations are found in this EGF precursor homology region.
Class 3 Mutations: Most of the class 3 alleles result from in-frame rearrangements in the cysteine-rich repeats of the LDL-binding domain or in the EGF precursor domain. Because there is a similarity in the class 2 and class 3 mutant alleles, it is difficult to assess which class of mutation is causing the observed FH phenotype. To accurately distinguish class 3 and class 2B alleles at the functional level it is necessary to isolate fibroblasts from the patient and do in vitro ligand-binding assays.
Class 4 Mutations: All of the class 4 alleles have been shown to affect the cytoplasmic domain of the LDLR protein. In addition, class 4 alleles can be divided into two subclasses dependent upon whether the mutations affect only the cytoplasmic domain or include mutations in the adjacent membrane-spanning domain.
Class 5 Mutations: Deletion or alteration of the EGF precursor homology domain results in class 5 alleles. The total percentage of FH alleles that are of the class 5 type may be underestimated because the class 5 mutations can produce a phenotype that somewhat resembles that of class 3 mutations (i.e. deficient LDL binding).