Homozygous inheritance of the Z-type mutant form of the α1-antitrypsin (α1AT) gene results hi the most common form of α1AT deficiency, a human hereditary disease associated with a high risk far the development of emphysema and an increased incidence of neonatal hepatitis. The α1AT-synthesizing cells of individuals with the Z gene have normal α1AT messenger RNA levels, but α1AT secretion is markedly reduced secondary to accumulation of newly synthesized α1AT in the rough endoplasmic reticulum. Crystallographic analysis of α1AT predicts that in normal α1AT, a negatively charged Glu342 is adjacent to positively charged Lys290. Thus the Glu342 → Lys 342 Z mutation causes the loss of a normal salt bridge, resulting in the intracellular aggregation of the Z molecule. The prediction was made that a second mutation in the α1AT gene that changed the positively charged Lys290 to a negatively charged Glu290 would correct the secretion defect. When the second mutation was added to the Z-type complementary DNA, the resulting gene directed the synthesis and secretion of amounts of α1AT similar to that directed by the normal α1AT complementary DNA in an in vitro eukaryotic expression system. This suggests the possibility that a human hereditary disease can be corrected by inserting an additional mutation in the same gene.
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