title: Molecular basis of alpha-1-antitrypsin deficiency.
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.
authors.affiliation: Pulmonary Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland 20892.
authors.forename: M
authors.initials: M
authors.lastname: Brantly
authors.forename: T
authors.initials: T
authors.lastname: Nukiwa
authors.forename: R G
authors.initials: RG
authors.lastname: Crystal
mesh_terms: D000483:Alleles; D005786:Gene Expression Regulation; D006801:Humans; D008107:Liver Diseases / Q000235:genetics; D011656:Pulmonary Emphysema / Q000235:genetics; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000502:physiology; D019896:alpha 1-Antitrypsin Deficiency
chemical_list: D000515:alpha 1-Antitrypsin