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 the mutation of chromosome 14.
Causes
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.