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

• Published in: Human molecular genetics 1993-03, Vol.2 (3), p.253-257
• Main Authors: Morgan, Kevin, Scobie, Graeme, Kalsheker, Noor A.
• Format: Article
• Language: English
• Subjects: alpha -1-antitrypsin; alpha 1-Antitrypsin - genetics; Base Sequence; Biological and medical sciences; Chronic Disease; chronic respiratory disease; DNA - genetics; Enhancer Elements, Genetic; genes; Humans; man; Medical sciences; Molecular Sequence Data; Pneumology; Point Mutation; regulatory; Regulatory Sequences, Nucleic Acid; Respiratory system : syndromes and miscellaneous diseases; Respiratory Tract Diseases - genetics; sequence
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/2.3.253

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.