α1-Antitrypsin deficiency and emphysema: In the United States, ~2%– 5% of patients with emphysema are predisposed to the disease by inherited defects in AAT. A number of different mutations in the gene for AAT are known to cause a deficiency of the protein, but one single purine base mutation (GAG to AAG, resulting in the substitution of lysine for glutamic acid at position 342 of the protein) is clinically the most widespread and severe. [Note: The mutated protein is termed the Z variant.] The mutation causes the normally monomeric AAT to misfold, polymerize, and aggregate within the RER of hepatocytes, resulting in decreased secretion of AAT by the liver. AAT deficiency is, therefore, a misfolded protein disease. Consequently, blood levels of AAT are reduced, decreasing the amount that gets to the lung. The polymer that accumulates in the liver may result in cirrhosis (scarring of the liver). In the United States, the AAT mutation is most common in Caucasians of Northern European ancestry. An individual must inherit two abnormal AAT alleles to be at risk for the development of emphysema. In a heterozygote, with one normal and one defective gene, the levels of AAT are sufficient to protect the alveoli from damage. [Note: Methionine 358 in AAT is required for the binding of the inhibitor to its target proteases. Smoking causes the oxidation and subsequent inactivation of the methionine, thereby rendering the inhibitor powerless to neutralize elastase. Smokers with AAT deficiency, therefore, have a considerably elevated rate of lung destruction and a poorer survival rate than nonsmokers with the deficiency.] The deficiency of elastase inhibitor can be treated by weekly augmentation therapy, that is, intravenous administration of AAT. The AAT diffuses from the blood into the lung, where it reaches therapeutic levels in the fluid surrounding the lung epithelial cells.
IV. CHAPTER SUMMARY
Collagen and elastin are structural fibrous proteins of the extracellular matrix (Fig. 4.15). Collagen contains an abundance of proline, lysine, and glycine, the latter occurring at every third position in the primary structure. It also contains hydroxyproline, hydroxylysine, and glycosylated hydroxylysine, each formed by posttranslational modification. Fibrillar collagen has a long, rigid structure, in which three collagen polypeptide α chains are wound around one another in a rope-like triple helix stabilized by interchain hydrogen bonds. Diseases of fibrillar collagen synthesis affect bones, joints, skin, and blood vessels. Elastin is a connective tissue protein with rubber-like properties in tissues such as the lung. α1-Antitrypsin (AAT), produced primarily by the liver, inhibits elastase-catalyzed degradation of elastin in the alveolar walls. A deficiency of AAT increases elastin degradation and can cause emphysema and, in some cases, cirrhosis of the liver.
Choose the ONE best answer.
.1. A 30-year-old woman of Northern European ancestry presents with progressive dyspnea (shortness of breath). She denies the use of cigarettes. Family history reveals that her sister also has problems with her lungs. Which one of the following etiologies most likely explains this patient’s pulmonary symptoms?
A. Deficiency in dietary vitamin C
B. Deficiency of α1-antitrypsin
C. Deficiency of prolyl hydroxylase
D. Decreased elastase activity
E. Increased collagenase activity