Deletion/frameshift mutation in the alpha 1-antitrypsin null allele, PI*QObolton

The most common deficiency allele of the protease inhibitor (PI) alpha 1-antitrypsin (alpha 1AT) is PI*Z. Other rare deficiency alleles of alpha 1AT are of two types: those producing low but detectable amounts of alpha 1AT (less than 20% of normal serum concentrations), and null alleles producing less than 1% of normal alpha 1AT and therefore not detectable by routine quantitative methods. We have previously used DNA polymorphisms and family data to determine heterozygosity in an individual producing low levels of serum alpha 1AT (12% of normal) of PI type Mmalton. By DNA analysis we observed the typical haplotype associated with PI*Mmalton and a unique null haplotype associated with the allele PI*QObolton. The QObolton allele produces no detectable serum alpha 1AT. We have cloned and sequenced the QObolton allele from a phage genomic library. Deletion of a single cytosine residue near the active site of alpha 1 AT in exon V results in a frameshift causing an in-frame stop codon downstream of the deletion. This stop codon leads to premature termination of protein translation at amino acid 373, resulting in a truncated protein. The truncated protein is predicted to have an altered carboxy terminus (amino acids 363-372) and will lack structurally important amino acids.