Alpha 1-antitrypsin deficiency causes

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]

Overview

Alpha 1-antitrypsin deficiency (A1AD) occurs largely in part because of a mutation of chromosome 14.

Causes

Alpha-1 antitrypsin (AAT) is a type of protein called a "protease inhibitor." It is made in the liver and it works to protect the lungs and liver. AAT deficiency means there is not enough of this protein in the body. It is caused by a genetic defect in the formation of the 14th chromosome.

Genetics

The alpha-1 AT gene has been located on the long arm of chromosome 14, and has been successfully been sequenced and cloned. There have been 75 different alleles for alpha-1 AT variants that have been described, but only 10-15 are associated with severe alpha-1 AT deficiency. Each allele has been given a letter code based upon electrophoretic mobility. By far, the most common severe deficient variant is the Z allele, which is produced by substitution of a lysine for glutamate at position 342 of the molecule. This accounts for 95% of the clinically recognized cases of severe alpha-1 AT deficiency. The 75 alleles can basically be divided into four groups:

• Normal – M alleles (normal phenotype is MM), found in 90% of the U.S. population, patients have normal lung function.
• Deficient – Z allele (carried by 2-3% of the U.S. Caucasian population), have plasma levels of alpha-1 AT that are < 35% of normal.
• Null – No detectable alpha-1 AT. Least common and most severe form of the disease.
• Dysfunctional – Patients have a normal alpha-1 AT level, but the enzyme does not function properly.