[Genetic analyses of alpha 1-antitrypsin deficiency]

The deficiency of alpha 1-antitrypsin, a strong protease inhibitor, is known to cause pulmonary emphysema, neonatal hepatitis and liver cirrhosis. Among 75 variants reported so far, amino acid or DNA variations have been determined in about 30 variants. Many are caused by single base substitutions which then cause single amino acid replacements. In most of the null variants, base substitutions, base deletions or base insertions make stop codons appear somewhere beyond the mutation sites, which cause truncated proteins. Only several variants, including PiZ and PiMmalton, characterized as having cytoplasmic globules in hepatocytes, cause liver diseases. Recent analyses on the tertiary structure of alpha 1-antitrypsin have elucidated the mechanism of the formation of insoluble polymers in PiZ patients. The accumulation theory seems more relevant to the mechanism of the liver damage than the protease-antiprotease imbalance theory.