Characterization of the M1(Ala213) type of .alpha.1-antitrypsin, a newly recognized, common "normal" .alpha.1-antitrypsin haplotype

Abstract

alpha 1-Antitrypsin (alpha 1AT) is a highly pleomorphic 52-kDa serum glycoprotein that functions as the major inhibitor of neutrophil elastase. Of these, the most common normal alpha 1AT haplotypes identified by isoelectric focusing (IEF) of serum are those of the M family, including M1, M2, and M3. In the course of studying the alpha 1AT type Z gene, we identified a restriction endonuclease BstEII polymorphism in the M1 gene that predicted the existence of a previously unidentified, but relatively common, haplotype of M, referred to as M1(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 alpha 1AT genes from an individual heterozygous for the M1(Ala213) and M1(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 M1(Ala213) gene was demonstrated in a family study. Evaluation of 39 genomic samples of Caucasians with the IEF haplotype M1 demonstrated haplotype frequencies of 68% for M1(Val213) and 32% for M1(Ala213). alpha 1AT serum levels of individuals inheriting the M1(Ala213) gene in a homozygous fashion were in the same range as those for homozygous M1(Val213) as was the rate of association of the M1(Ala213) protein with neutrophil elastase.(ABSTRACT TRUNCATED AT 250 WORDS)

Compound Heterozygosity for Alpha-1-antitrypsin (Siiyama and QOclayton) in an Oriental Patient.

“…The lack of a Z allele in Japan, in contrast to Caucasian populations, might be explained by the difference between Caucasians and Japanese concerning a unique mutation of an allelic marker, Ala213 (GCG) /Val213 (GIG). Although a Z deficient allele carries Ala2 13 on its alAT backbone structure and approximately one-third of Caucasians with Ml haplotypes in the United States have Ala213 (18,19), none of the Japanese subjects examined (386 haplotypes) carried Ala213. Instead, all of these Japanese carried Val213, including a Siiyama deficient variant (7).…”

Fate of aerosolized recombinant DNA-produced alpha 1-antitrypsin: use of the epithelial surface of the lower respiratory tract to administer proteins of therapeutic importance.

“…The rAAT used in these studies was produced by yeast transformed with an expressing plasmid containing a human cDNA encoding the mature normal Ml (Val213) human a1-antitrypsin protein (23)(24)(25). The expressing plasmid pFATPOT was transformed into a Saccharomyces cerevisiae strain to yield zymosan-3, a diploid yeast strain containing the pFATPOT construct (Cooper Laboratories) (23).…”

Genetics of ?1 Anti-Trypsin (AAT) Deficiency

“…When two alleles have an identical IEF pattern and the sequence difference is known, the relevant residue is specifically indicated [11]. For example; the two most common AAT alleles, M1 (Val213) and M1 (Ala213), have IEF patterns of M1, but differ at residue 213 by the neutral amino acids valine and alanine [12]. Some rare alleles are labeled by a letter indicating the IEF position together with the birth site of the allele (e.g.…”

“…AAT 'at risk' alleles had been divided into 'deficiency' alleles and 'null' alleles [11]. The most common AATD allele is the Z allele (glu 342 lys), which occurs on an M1Ala213 haplotype [12]. Homozygous ZZ is at high risk of both emphysema and liver disease; Z allele is polymorphic in Caucasians but rare in Asians and blacks [13].…”

“…AAT gene in null/null cases was found structurally intact but with no detectable mRNA; no epigenetic abnormality in promoter region or hypermethylation of cytosine, so it was explained by failure of excretion of the abnormal AAT outside cells of origin [15]. Null (Granite Falls) results from a frame-shift mutation causing a stop codon [12]. Early onset emphysema was reported in three families presumed to be related to passive smoking, however they showed no detectable AAT protein with unexpectedly no major gene deletion [16].…”