Characterization of the molecular basis of the alpha 1-antitrypsin F allele.

alpha 1-Antitrypsin (alpha 1AT), the major serum inhibitor of neutrophil elastase, is a highly polymorphic serum protein associated with characteristic isoelectric-focusing (IEF) patterns for most variants. To characterize the molecular basis of the anodal F variant, the DNA sequence of the coding exons of an FZ individual was determined. The F allele differed from the normal M1(Val213) alpha 1AT allele by a single nucleotide transversion of cytosine to thymidine, which results in the amino acid substitution Arg223 CGT----Cys TGT. Inheritance of the F mutation was confirmed by family analysis using allele-specific amplification. In the context that the normal alpha 1AT molecule has only one cysteine residue, a mutation resulting in the addition of a second cysteine may influence the three-dimensional form of the protein and/or permit interaction with other plasma proteins with free-SH groups and may be responsible for the observation that the major F alpha 1AT bands often migrate as doublets in IEF gels.