A null deficiency allele of alpha 1-antitrypsin, QOludwigshafen, with altered tertiary structure.

The most common deficiency allele of the plasma protease inhibitor alpha 1-antitrypsin (alpha 1AT) is PI*Z. Some rare deficiency alleles of alpha 1AT produce low but detectable amounts of plasma alpha 1AT (1-20% of normal), which can be differentiated by isoelectric focusing. Others, designated null (QO) alleles, produce no alpha 1AT detectable by routine quantitative methods. We have previously described a method using DNA polymorphisms, haplotypes, and polyacrylamide isoelectric focusing gels, to differentiate various deficiency alleles. Based on haplotypes, we previously identified, in eight patients, five different null alleles, four of which had been previously sequenced. We have now analyzed all 12 null alleles in these eight patients, using allele-specific oligonucleotide probes, and have identified six different null alleles. We have cloned and sequenced one of these, PI*QOludwigshafen, which has a base substitution in exon II, replacing isoleucine 92 in the normal sequence with an asparagine. This substitution of a polar for a nonpolar amino acid occurs in one of the alpha-helices and is predicted to disrupt the tertiary structure. A total of 13 different alpha 1AT deficiency alleles, 6 of them null alleles, have been sequenced to date.