The Mmineral springs α1-antitrypsin (α1AT) allele, causing α1AT deficiency and emphysema, is unique among the α1AT-deficiency alleles in that it was observed in a black family, whereas most mutations causing α1AT deficiency are confined to Caucasian populations of European descent. Immobilized pH gradient analysis of serum demonstrated that α1AT Mmineral springs migrated cathodal to the normal M2 allele. Evaluation of Mmineral springs α1AT as an inhibitor of neutrophil elastase, its natural substrate, demonstrated markedly lower than normal function. Characterization of the α1AT Mmineral springs gene demonstrated that it differed from the common normal M1(Ala213) allele by a single-base substitution causing the amino acid substitution Gly-67 (GGG)→Glu-67 (GAG). Capitalizing on the fact that this mutation creates a polymorphism for the restriction endonuclease AvaII, family analysis demonstrated that the Mmineral springs α1AT allele was transmitted in an autosomal-codominant fashion. Evaluation of genomic DNA showed that the index case was homozygous for the α1ATMmineral springs allele. Cytoplasmic blot analysis of blood monocytes of the Mmineral springs homozygote demonstrated levels of α1AT mRNA transcripts comparable to those in cells of a normal M1(Val213) homozygote control. Evaluation of in vitro translation of Mmineral springs α1AT mRNA transcripts demonstrated a normal capacity to direct the translation of αAT. Evaluation of secretion of α1AT by the blood monocytes by pulse-chase labeling with [35S]methionine, however, demonstrated less secretion by the Mmineral springs cells than normal cells. To characterize the posttranslational events causing the α1AT-secretory defect associated with the α1AT Mmineral springs gene, retroviral gene transfer was used to establish polyclonal populations of murine fibroblasts containing either a normal human M1 α1AT cDNA or an Mmineral springs α1AT cDNA and expressing comparable levels of human α1AT mRNA transcripts. Pulse-chase labeling of these cells with [35S]methionine demonstrated less secretion of human α1AT from the Mmineral springs cells than from the M1 cells, and evaluation of cell lysates also demonstrated lower amounts of intracellular human α1AT in the Mmineral springs cells tnan in the normal M1 control cells. Thus, the Gly-67→Glu mutation that characterizes Mmineral springs causes reduced α1AT secretion on the basis of aberrant posttranslational α1AT biosynthesis by a mechanism distinct from that associated with the α1AT Z allele, whereby intracellular aggregation of the mutant protein is etiologic of the α1AT-secretory defect. Furthermore, for the α1AT protein that does reach the circulation, this mutation markedly affects the ability of the molecule to inhibit neutrophil elastase; i.e., the α1AT Mmineral springs allele predisposes to emphysema on the basis of serum α1AT deficiency coupled with α1AT dysfunction.

Original languageEnglish
Pages (from-to)47-56
Number of pages10
JournalMolecular and cellular biology
Issue number1
StatePublished - Jan 1990


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