THE HUMAN α1-ANTITRYPSIN GENE AND PULMONARY EMPHYSEMA

Publisher Summary This chapter describes alpha-l-antitrypsin as a protease inhibitor that accounts for 90% of the total anti-protease activity in the blood. It is transported by passive diffusion into the alveolar structure of the lung and protects it from destruction by polymorphonuclear leukocyte elastase. Reduced levels of this protein in certain individuals constitute a genetic disorder known as α 1-antitrypsin deficiency, which is often associated with development of chronic obstructive pulmonary emphysema. This deficiency is characterized by the presence of a mutated α 1-antitrypsin gene that gives rise to a variant ζ type protein instead of the normal M type protein and is inherited by an autosomal recessive trait. Alpha-l-antitrypsin is a single polypeptide of 45,000 daltons in molecular weight and is synthesized in the liver. A total of 21 Kb of human DNA is represented in these overlapping genomic clones, with 8 Kb of DNA flanking the 5´ and 3´ termini of the α 1-antitrypsin gene. Electronmicroscopic and restriction mapping analyses have shown that the human chromosomal α 1-antitrypsin gene contains three intervening sequences and is approximately 5 Kb in length. The entire gene resides within a 9.6 Kb Eco RI fragment, which facilitates the cloning of the chromosomal gene from deficient individuals. The human chromosomal α 1-antitrypsin gene has been used as a probe to analyze the deficiency syndrome at the gene level to develop gene mapping methods for prenatal diagnosis of the genetic disorder.