Point mutation in a 3′ flanking sequence of the alpha-1-antitrypsin gene associated with chronic respiratory disease occurs in a regulatory sequence

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Abstract
A point mutation in the 3′ flanking sequence of the alpha-1-antitrypsin gene is associated with chronic respiratory disease. This study demonstrates that the mutation occurs in a motif that binds a nuclear factor. A direct consequence of the mutation is the loss of specific binding. Functional studies with constructs containing this region downstream of a reporter gene in the sense orientation demonstrated that the wild type sequence increased expression compared with control promoter plasmid and there was a significant reduction in expression by the mutant sequence. These effects were demonstrated in three distinct cell lines suggesting an ubiquitous rather than a tissue-specific effect. However, trans-acting factors may influence the response in different tissues. The mutation does not appear to affect basal expression of the protein as the plasma concentration of alpha-1-antitrypsin is normal in individuals who carry the mutation. However, the binding and functional studies suggest that it may reduce the three- to four-fold rise in plasma alpha-1-antitrypsin concentration that occurs during inflammation.

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