Identification of a second mutation in the protein-coding sequence of the Z type alpha 1-antitrypsin gene

T. Nukiwa, K. Satoh, M. L. Brantly, F. Ogushi, G. A. Fells, M. Courtney, R. G. Crystal

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This study reports the entire nucleotide sequence of the protein coding region sequence of the alpha 1-antitrypsin (α1AT) Z gene, a common form of the α1AT gene associated with serum α1AT deficiency. In addition to Glu342 to Lys342 mutation in exon V which has been previously identified by peptide analysis, another point mutation (GTG to GCG in exon III) in the gene sequence predicts a second amino acid substitution (Val213 to Ala213) in the Z protein. This Val213 to Ala213 mutation was confirmed to be a general finding in Z type α1AT gene by evaluating genomic DNA from 40 Z haplotypes using synthetic oligonucleotide gene probes directed toward the mutated exon III sequences in the Z gene. Furthermore, the exon III Val213 to Ala213 mutation eliminates a BstEII restriction endonuclease site in the α1AT Z gene, allowing rapid identification of this Val213 to Ala213 substitution at the genomic DNA level. Suprisingly, when genomic DNA samples from individuals thought to be homozygous for the M1 gene (the most common α1AT normal haplotype) were evaluated with BstEII, 23% of the M1 haplotypes were BstEII site negative, thus identifying a new form of M1 (i.e. M1(Ala213)), likely identical to M1 but with an isoelectric focusing 'silent' amino acid substitution (Val213 to Ala213). Although the relative importance of the newly identified exon III Val213 to Ala213 mutation to the pathogenesis of the abnormalities associated with the Z gene is not known, it is likely that M1(Ala213) gene represents a common 'normal' polymorphism of the α1AT gene that served as an evolutionary intermediate between the M1(Val213) and Z genes.

Original languageEnglish
Pages (from-to)15989-15994
Number of pages6
JournalJournal of Biological Chemistry
Issue number34
Publication statusPublished - 1 Dec 1986


ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Nukiwa, T., Satoh, K., Brantly, M. L., Ogushi, F., Fells, G. A., Courtney, M., & Crystal, R. G. (1986). Identification of a second mutation in the protein-coding sequence of the Z type alpha 1-antitrypsin gene. Journal of Biological Chemistry, 261(34), 15989-15994.