Am J Med 1988 Jun 24;84(6A):13-31

Molecular basis of alpha-1-antitrypsin deficiency

Brantly M, Nukiwa T, Crystal RG
Pulmonary Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland
20892

Abstract
Alpha-1-antitrypsin (A1AT) deficiency is an autosomal hereditary disorder
associated with a major reduction in serum A1AT levels. Clinically, A1AT
deficiency is associated with emphysema in adults and, less commonly, liver
disease in neonates. A1AT is a 52-kDa, 394-amino acid, single-chain glycoprotein
normally present in serum at 150 to 350 mg/dl. The A1AT gene, composed of seven
exons dispersed over 12 kb of chromosomal segment 14q31-32.3, is expressed in
hepatocytes and mononuclear phagocytes. The A1AT protein, a member of the class
of protease inhibitor proteins known as serpins (serine protease inhibitors), is
a globular molecule composed of nine alpha-helices and three beta-pleated
sheets. The major function of A1AT is to inhibit neutrophil elastase; A1AT does
so through an active site centered around Met358 contained within an external
stressed loop on the surface of the molecule. A1AT is a highly pleomorphic
protein with greater than 75 variants determined at the protein and/or gene
level. These variants can be categorized into four groups according to their
serum A1AT level and function: normal, deficient, dysfunctional, and absent.
There are two important salt bridges within the A1AT molecule (Glu342-Lys290;
Glu263-Lys387); a mutation in the A1AT gene causing disruption of either salt
bridge causes distinct molecular pathology resulting in reduced serum A1AT
levels. Clinically relevant variants can be distinguished by a combination of
isoelectric focusing of serum, restriction fragment length analysis of genomic
DNA, oligonucleotide probes, and direct sequencing of the variant A1AT genes