Molecular Diagnosis of Cardiovascular Disorders - Applications of Biotechnology in Cardiovascular Therapeutics - page 140

Gene Mutations and Disturbances of Blood Lipids
Hundreds of mutations have been reported in genes encoding apolipoproteins,
lipolytic enzymes, and lipoprotein receptors. Such defects can cause serious pertur-
bations in blood lipid concentrations.
Familial Dyslipoproteinemias
These have been characterized at the molecular level. For instance, functional poly-
morphism of apolipoprotein E (encoded on chromosome 19q13) can be assessed by
PCR. In the normal population, polymorphism of E2, E3, and E4 exerts a substantial
effect on the normal variations in the plasma lipid concentrations, accounting for
16% of the genetic variation in cholesterol concentration. An age-related increase
of E2 allele and a decrease of E4 allele, for example, may contribute to the increased
number of deaths from myocardial infarction. Homozygosity of the E2 allele,
occurring in association with diabetes mellitus, hypothyroidism, or other genetic
defect of lipid metabolism, can lead to dysbetalipoproteinemia (type III hyperlipi-
demia); this condition is characterized by profound hypertriglyceridemia, moderate
hypercholesterolemia, and premature CHD.
Lipoprotein (a) may be a monogenic risk factor for CHD, accounting for a major
portion of the familial predisposition to CHD that cannot be explained by other
factors. The Apo (a) gene locus determines more than 90% of the variations in
plasma lipoprotein (a) concentration.
Hypercholesterolemia
Individuals with familial hypercholesterolemia (FH) manifest defective catabolism
of low-density lipoprotein (LDL), which increases plasma circulating LDL choles-
terol levels two- to threefold. This rise in LDL levels may cause cholesterol to be
deposited in the arterial wall, leading to premature atherosclerosis and CHD.
Predictive identification of at-risk individuals is important because prophylactic
treatment with cholesterol-lowering drugs can reduce morbidity and mortality. One
of the most common single-gene disorders, heterozygous FH, affects approxi-
mately 1 in 500 individuals.
Mutations in the LDL gene are a major cause of FH, and more than 300 different
point mutations and short deletions in this gene have been characterized to date.
One such mutation found in the Finnish population (FH-North Karelia) deletes
seven nucleotides from exon 6 of the LDL receptor gene. PCR amplification of
DNA samples from patients with this condition prompted the formation of DNA
heteroduplexes that markedly improved mutation detection. Multiplex PCR,