I 6.6 Low-density lipoprotein (LDL) particles transport cholesterol.
The LDL receptor moves LDL through the cell membrane into the cytoplasm.
in cholesterol transport. Cholesterol is an essential component of cell membranes and is used in the synthesis of bile salts and several hormones. Most of our cholesterol is obtained through foods, primarily those high in saturated fats. Because cholesterol is a lipid (a nonpolar, or uncharged, compound), it is not readily soluble in the blood (a polar, or charged, solution). Cholesterol must therefore be transported throughout the body in small soluble particles called lipoproteins ( FIGURE 6.6); a lipoprotein consists of a core of lipid surrounded by a shell of charged phospholipids and proteins that dissolve easily in blood. One of the principle lipoproteins in the transport of cholesterol is low-density lipoprotein (LDL). When an LDL molecule reaches a cell, it attaches to an LDL receptor, which then moves the LDL through the cell membrane into the cytoplasm, where it is broken down and its cholesterol is released for use by the cell.
Familial hypercholesterolemia is due to a defect in the gene (located on human chromosome 19) that normally codes for the LDL receptor. The disease is usually considered an autosomal dominant disorder because heterozygotes are deficient in LDL receptors. In these people, too little cholesterol is removed from the blood, leading to elevated blood levels of cholesterol and increased risk of coronary artery disease. Persons heterozygous for familial hypercholes-terolemia have blood LDL levels that are twice normal and usually have heart attacks by the age of 35. About 1 in 500 people is heterozygous for familial hypercholesterolemia and is predisposed to early coronary artery disease.
Very rarely, a person inherits two defective LDL receptor alleles. Such persons don't make any functional LDL receptors; their blood cholesterol levels are more than six times normal and they may suffer a heart attack as early as age 2 and almost inevitably by age 20. Because homozygotes are more severely affected than heterozygotes, familial hypercholesterolemia is said to be incompletely dominant. However, homozygotes are rarely seen (occurring with a frequency of only about 1 in 1 million people), and the common heterozygous form of the disease appears as a simple dominant trait in most pedigrees.
X-linked recessive traits have a distinctive pattern of inheritance ( FIGURE 6.7). First, these traits appear more frequently in males, because males need inherit only a single copy of the allele to display the trait, whereas females must inherit two copies of the allele, one from each parent, to be affected. Second, because a male inherits his X chromosome from his mother, affected males are usually born to unaffected mothers who carry an allele for the trait. Because the trait is passed from unaffected female to affected male to unaffected female, it tends to skip generations (see Figure 6.7). When a woman is heterozygous, approximately / of her sons will be affected and / of her daughters will be unaffected carriers. For example, we know that females I-2, II-2, and III-7 in Figure 6.7 are all carriers because they transmit the trait to approximately half of their sons.
A third important characteristic of X-linked recessive traits is that they are not passed from father to son, because a son inherits his father's Y chromosome, not his X. In Figure 6.7, there is no case of a father and son who are both affected. All daughters of an affected man, however, will be carriers (if their mother is homozygous for the normal allele). When a woman displays an X-linked trait, she must be homozygous for the trait, and all of her sons will also display the trait.
Rare X-linked recessive traits appear more often in males than in females and are not passed from father to son. Affected sons are usually born to unaffected mothers; thus X-linked recessive traits tend to skip generations.
An example of an X-linked recessive trait in humans is hemophilia A, also called classical hemophilia ( FIGURE 6.8). This disease results from the absence of a protein necessary for blood to clot. The complex process of blood clotting consists of a cascade of reactions that includes more than 13 different factors. For this reason, there are several types of clotting disorders, each due to a glitch in a different step of the clotting pathway.
Hemophilia A results from abnormal or missing factor VIII, one of the proteins in the clotting cascade. The gene for factor VIII is located on the tip of the long arm of the X chromosome; so hemophilia A is an X-linked recessive disorder. People with hemophilia A bleed excessively; even small cuts and bruises can be life threatening. Spontaneous bleeding occurs in joints such as elbows, knees, and ankles, which produces pain, swelling, and erosion of
An affected male does not pass the trait to his sons...
. but can pass the allele to a daughter, who is unaffected.
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