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Genetics students assignment. Yoav Stark GR 2 1 antitrypsin deficiency This condition is inherited in an autosomal codominant pattern. Mutations in the SERPINA1 gene cause alpha-1 antitrypsin deficiency. The SERPINA1 gene is located on the long (q) arm of chromosome 14 at position 32.1. Size: 418 amino acids Molecular Location on chromosome 14: base pairs 94,843,083 to 94,857,028 Length: 13,946 it's a protease inhibitor belonging to the serpin superfamily. It is generally known as serum trypsin inhibitor. Alpha 1antitrypsin is also referred to as alpha-1 proteinase inhibitor (A1PI) because it inhibits a wide variety of proteases. It protects tissues from enzymes of inflammatory cells, especially neutrophil elastase. In its absence, neutrophil elastase is free to break down elastin, which contributes to the elasticity of the lungs, resulting in respiratory complications such as emphysema, or COPD (chronic obstructive pulmonary disease) in adults and cirrhosis in adults or children. More than 120 mutations in the SERPINA1 gene have been identified. Some of these mutations do not affect the production of alpha-1 antitrypsin, while others cause a shortage (deficiency) of the protein. Without enough functional alpha-1 antitrypsin, neutrophil elastase destroys the small air sacs in the lungs (alveoli) and causes lung disease. Excessive damage to the alveoli leads to emphysema, an irreversible lung disease that causes extreme shortness of breath. Many SERPINA1 gene mutations change single protein building blocks (amino acids) in alpha-1 antitrypsin, which alters the protein's structure. The most common mutation that causes alpha-1 antitrypsin deficiency replaces the amino acid glutamic acid with the amino acid lysine at protein position 342 (written as Glu342Lys or E342K). This mutation results in a version of theSERPINA1 gene called the Z allele that produces very little alpha-1 antitrypsin. Abnormal alpha-1 antitrypsin proteins may bind together to form a large molecule, or polymer, that cannot leave the liver. The accumulation of these polymers results in liver damage. In addition, lung tissue is destroyed because not enough alpha-1 antitrypsin is available to protect against neutrophil elastase. Polymers of alpha-1 antitrypsin may also contribute to excessive inflammation, which may explain some of the other features of alpha-1 antitrypsin deficiency, such as a skin condition called panniculitis. Other SERPINA1 gene mutations lead to the production of an abnormally small form of alpha-1 antitrypsin that is quickly broken down in the liver. As a result, little or no alpha-1 antitrypsin is available in the lungs. While the liver remains healthy in individuals with these mutations, the lungs are left unprotected from neutrophil elastase.

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DeCroo et al. (1991) studied the frequency of alpha-1-antitrypsin alleles in US whites, US blacks, and African blacks (living in Nigeria). While the PI*S allele was present at a polymorphic level in US whites, it was present only sporadically in US blacks and completely absent in African blacks. Another common AAT deficiency allele is the S allele (glu264-to-val; 107400.0013), which occurs on an M1V (val213; 107400.0002) haplotype background. Pi*S homozygotes are at no risk of emphysema, but compound heterozygotes with a Z or a null allele have a mildly increased risk (Curiel et al., 1989). The S allele reaches polymorphic frequencies in Caucasians and is rare or absent in Asians and blacks. It is not associated with liver disease. Its primary manifestation is early-onset panacinar emphysema. About 1-3% of patients with diagnosed chronic obstructive pulmonary disease (COPD) are predicted to have alpha1-antitrypsin deficiency. Slowly progressive dyspnea is the primary symptom, though many patients initially have symptoms of cough, sputum production, or wheezing. Treatment involves smoking cessation, bronchodilation, and physical rehabilitation in a program similar to that designed for patients with smoking-related COPD. In addition, intravenous (IV) augmentation therapy with alpha1antitrypsin benefits some patients. Alpha1-antitrypsin deficiency is also an unusual cause of hepatic cirrhosis in children and adults.