α1-Antitrypsin Wbethesda: Molecular basis of an unusual α1-antitrypsin deficiency variant

M. D. Holmes, M. L. Brantly, G. A. Fells, Ronald Crystal

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Molecular analysis of α1-antitrypsin (α1AT) Wbethesda revealed that it differs from the normal M1(A1a213) allele by a single base mutation causing an amino acid substitution A1a336GCT → Thr ACT. Evaluation of α1AT biosynthesis directed by the Wbethesda allele showed that although Wbethesda α1AT mRNA was translated normally invitro, transfection of the Wbethesda cDNA into COS-I cells was associated with human α1AT secretion of 50% that of cells transfected with a normal α1AT cDNA. The pattern of α1AT biosynthesis was not intracellular accumulation as observed with the common Z α1AT deficiency allele, but reduced intracellular α1AT, suggesting intracellular degradation of the newly synthesized Wbethesda molecule. Together these observations suggest that in heterozygous combination with a Z or Null α1AT allele, the Wbethesda variant causes "α1AT deficiency", thus classifying it as an α1AT "at risk" allele for emphysema.

Original languageEnglish
Pages (from-to)1013-1020
Number of pages8
JournalBiochemical and Biophysical Research Communications
Volume170
Issue number3
DOIs
Publication statusPublished - 16 Aug 1990
Externally publishedYes

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Biosynthesis
Complementary DNA
Alleles
Substitution reactions
Amino Acids
Degradation
Messenger RNA
Molecules
COS Cells
Emphysema
Amino Acid Substitution
Transfection
Mutation

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

α1-Antitrypsin Wbethesda : Molecular basis of an unusual α1-antitrypsin deficiency variant. / Holmes, M. D.; Brantly, M. L.; Fells, G. A.; Crystal, Ronald.

In: Biochemical and Biophysical Research Communications, Vol. 170, No. 3, 16.08.1990, p. 1013-1020.

Research output: Contribution to journalArticle

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AB - Molecular analysis of α1-antitrypsin (α1AT) Wbethesda revealed that it differs from the normal M1(A1a213) allele by a single base mutation causing an amino acid substitution A1a336GCT → Thr ACT. Evaluation of α1AT biosynthesis directed by the Wbethesda allele showed that although Wbethesda α1AT mRNA was translated normally invitro, transfection of the Wbethesda cDNA into COS-I cells was associated with human α1AT secretion of 50% that of cells transfected with a normal α1AT cDNA. The pattern of α1AT biosynthesis was not intracellular accumulation as observed with the common Z α1AT deficiency allele, but reduced intracellular α1AT, suggesting intracellular degradation of the newly synthesized Wbethesda molecule. Together these observations suggest that in heterozygous combination with a Z or Null α1AT allele, the Wbethesda variant causes "α1AT deficiency", thus classifying it as an α1AT "at risk" allele for emphysema.

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