α1-Antitrypsin (alAT) is a highly pleomorphic 52-kDa serum glycoprotein that functions as the major inhibitor of neutrophil elastase. Of these, the most common normal alAT haplotypes identified by isoelectric focusing (IEF) of serum are those of the M family, including Ml, M2, and M3. In the course of studying the alAT type Z gene, we identified a restriction endonuclease BstEII polymorphism in the Ml gene that predicted the existence of a previously unidentified, but relatively common, haplotype of M, referred to as Ml (Ala213) [Nukiwa, T., Satoh, K., Brantly, M. L., Ogushi, F., Fells, G. A., Courtney, M., & Crystal, R. G. (1986) J. Biol. Chem. 261, 15989–15994]. In this study we have cloned both alAT genes from an individual heterozygous for the Ml (Ala213) and Ml(Val213) haplotypes. Sequencing of the coding exons of both demonstrated that they are identical except for the Ala-Val difference at residue 213. The codominant transmission of the Ml (Ala213) gene was demonstrated in a family study. Evaluation of 39 genomic samples of Caucasians with the IEF haplotype Ml demonstrated haplotype frequencies of 68% for Ml(Val213) and 32% for Ml(Ala213). alAT serum levels of individuals inheriting the Ml(Ala213) gene in a homozygous fashion were in the same range as those for homozygous Ml(Val213) as was the rate of association of the Ml (Ala213) protein with neutrophil elastase. Interestingly, comparison of the Ml (Ala213) gene sequence to all of the known alAT sequences at the gene, cDNA, and protein levels demonstrated that Ml(Ala213) is the closest to the baboon alAT coding exons, suggesting that Ml(Ala213) is the “oldest” type human alAT known.
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