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Genetics

Alpha-1 Antitrypsin Deficiency, or Alpha-1, is an inherited, genetic condition that is passed on from generation to generation.

In order to be classified as having Alpha-1, an individual must inherit at least one abnormal AAT gene. Individuals who have one abnormal AAT gene and one normal AAT gene are sometimes referred to as heterozygotes or “carriers.”

Many of the risk factors that can lead to disease in Alphas are known, and the management of these risk factors is one of the most important ways in which individuals with Alpha-1 can directly affect the quality of their lives. Recently, there has been a growing appreciation that individuals who have been identified as carriers of the Alpha-1 gene also may be at increased risk for disease development. Therefore, limiting exposure to environmental risk factors is important for these individuals as well.

The severity of Alpha-1 is a function of the type of abnormal Alpha-1 genes inherited. Under a system called “Pi-typing,” numerous types of AAT genes have been identified and named, allowing for each type to be studied and evaluated. For example, the AAT genes Z and Null represent two Pi-types that are often associated with severe AAT deficiencies. Another type of AAT gene, the F Pi-type, produces a form of Alpha-1 in which the amount of AAT in the blood is normal, but the AAT does not perform properly. Interestingly, there also are abnormalities of the AAT gene that do not affect either the blood levels of the AAT protein or how the AAT functions.

Introduction to Alpha-1 – Big Fat Reference Guide

The gene for α1-AT is located on chromosome 14, and mutations at the protease inhibitor (PI) locus lead to a single amino acid substitution (glutamic acid for lysine 342) that impairs secretion of the mutant gene product, leading to retention of α1-AT in the hepatocyte and low levels of α1-AT in the serum. Because the phenotype is expressed by autosomal codominant inheritance, each allele is responsible for 50% of the circulating α1-AT level. Approximately 100 allelic variants have been described, only some of which are associated with liver disease.

Alpha1-Antitrypsin Deficiency – Cleveland Clinic

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