Home LiteratureArticle Details
PMID: 2901226 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Characterization of the gene and protein of the common alpha 1-antitrypsin normal M2 allele.

American journal of human genetics ·Vol. 43 ·No. 3 ·1988-09-00 ·Pages 322-30

Nukiwa T, Brantly ML, Ogushi F, Fells GA, Crystal RG

Abstract

The normal M2 variant of alpha 1-antitrypsin (alpha 1AT) was cloned from a genomic DNA library of an individual homozygous for this allele. Sequencing of all coding exons of the M2 gene revealed it was identical to the common M1(Val213) gene except for two bases (M1(Val213) CGT Arg101, M2 CAT His101; M1(Val213) GAA Glu376 M2 GAC Asp376). Analysis of the sequence of the M1(Val213) and M2 genes around residue 101 revealed the M1 Arg101----M2 His101 caused a loss of the cutting site for the restriction endonuclease RsaI. Using this enzyme, as well as 19-mer oligonucleotides probes centered at residues 101 and 376, evaluation of genomic DNA from 22 M1 alleles and 14 M2 alleles revealed that residue 101 was Arg in all M1 alleles and His in all M2 alleles, while residue 376 was Glu in all M1 alleles and Asp in all M2 alleles. Despite the differences in sequence at two amino acids, the M1(Val213) and M2 proteins function similarly as assessed by quantification of the association rate constant of each for their natural substrate neutrophil elastase. In the context that there are two mutations separating the M1(Val213) and M2 alleles, it is likely that there is another alpha 1AT variant that was an intermediate in the evolution of these genes.

MeSH Terms
Alleles Amino Acid Sequence Base Sequence Cloning, Molecular Genes Humans Isoelectric Point Molecular Sequence Data Pancreatic Elastase/metabolism Polymorphism, Restriction Fragment Length Protein Binding alpha 1-Antitrypsin/genetics
Chemicals
alpha 1-Antitrypsin Pancreatic Elastase
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Nukiwa T
Pulmonary Branch, National Heart, Lung, and Blood Institute, Bethesda, MD 20892.
Brantly M L
Ogushi F
Fells G A
Crystal R G
References (41)
41 references, click to expand
  1. Detection of specific sequences among DNA fragments separated by gel electrophoresis.
    J Mol Biol. 1975 Nov 5;98(3):503-17 PMID: 1195397
  2. Molecular basis of alpha-1-antitrypsin deficiency.
    Am J Med. 1988 Jun 24;84(6A):13-31 PMID: 3289385
  3. Labeling deoxyribonucleic acid to high specific activity in vitro by nick translation with DNA polymerase I.
    J Mol Biol. 1977 Jun 15;113(1):237-51 PMID: 881736
  4. Classification of alpha1-antitrypsin (Pi) phenotypes by isoelectrofocusing. Distinction of six subtypes of the PiM phenotype.
    Hum Genet. 1977 Oct 14;38(3):325-32 PMID: 303228
  5. DNA sequencing with chain-terminating inhibitors.
    Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463-7 PMID: 271968
  6. Reliable classification of six Pi M subtypes by separator isoelectric focusing.
    Hum Hered. 1978;28(3):201-9 PMID: 306379
  7. Structural evidence for methionine at the reactive site of human alpha-1-proteinase inhibitor.
    J Biol Chem. 1978 Oct 25;253(20):7142-4 PMID: 701239
  8. Alpha1-antitrypsin: further genetic heterogeneity revealed by isoelectric focusing.
    Am J Hum Genet. 1978 Jul;30(4):359-65 PMID: 309724
  9. An alpha 1-antitrypsin variant, Pi B Alhambra (Lys to Asp, Glu to Asp), with rapid anodal electrophoretic mobility.
    Am J Hum Genet. 1979 Sep;31(5):555-63 PMID: 315708
  10. Structural difference between the normal PiM1 and the common PiM2 variant of human alpha 1-antitrypsin.
    Am J Hum Genet. 1979 Sep;31(5):564-8 PMID: 315709
  11. Report of Nomenclature Meeting for alpha 1-antitrypsin, INSERM, Rouen/Bois-Guillaume-1978.
    Hum Genet. 1980;53(3):429-33 PMID: 6102963
  12. Kinetics of association of serine proteinases with native and oxidized alpha-1-proteinase inhibitor and alpha-1-antichymotrypsin.
    J Biol Chem. 1980 May 10;255(9):3931-4 PMID: 6989830
  13. Pi M4: an additional Pi M subtype.
    Hum Genet. 1980;55(1):119-21 PMID: 6969686
  14. The Pi polymorphism: genetic, biochemical, and clinical aspects of human alpha 1-antitrypsin.
    Adv Hum Genet. 1981;11:1-62, 371-2 PMID: 6168185
  15. Cloning and sequence of cDNA coding for alpha 1-antitrypsin.
    Proc Natl Acad Sci U S A. 1981 Nov;78(11):6826-30 PMID: 7031661
  16. Human alpha 1-antitrypsin: carbohydrate attachment and sequence homology.
    FEBS Lett. 1981 Dec 7;135(2):301-3 PMID: 6976274
  17. Sequence homology and structural comparison between the chromosomal human alpha 1-antitrypsin and chicken ovalbumin genes.
    Nature. 1982 Jun 24;297(5868):655-9 PMID: 6979715
  18. Structure and variation of human alpha 1-antitrypsin.
    Nature. 1982 Jul 22;298(5872):329-34 PMID: 7045697
  19. Human plasma proteinase inhibitors.
    Annu Rev Biochem. 1983;52:655-709 PMID: 6193754
  20. The isolation of a clone for human alpha 1-antitrypsin and the detection of alpha 1-antitrypsin in mRNA from liver and leukocytes.
    Biochem Biophys Res Commun. 1983 Oct 31;116(2):375-82 PMID: 6606425
  21. High-level production of biologically active human alpha 1-antitrypsin in Escherichia coli.
    Proc Natl Acad Sci U S A. 1984 Feb;81(3):669-73 PMID: 6322161
  22. Human alpha 1-proteinase inhibitor. Crystal structure analysis of two crystal modifications, molecular model and preliminary analysis of the implications for function.
    J Mol Biol. 1984 Aug 15;177(3):531-57 PMID: 6332197
  23. Distribution of alpha 1-antitrypsin variants in a US white population.
    Hum Hered. 1984;34(5):308-10 PMID: 6332773
  24. Revised sequence of full-length complementary DNA coding for human alpha 1-antitrypsin.
    DNA. 1984 Aug;3(4):327-30 PMID: 6333329
  25. A new method for determination of alpha-1-antitrypsin phenotypes using isoelectric focusing on polyacrylamide gel slabs.
    Am J Clin Pathol. 1974 Dec;62(6):732-9 PMID: 4215312
  26. Synthesis in yeast of a functional oxidation-resistant mutant of human alpha-antitrypsin.
    Nature. 1984 Nov 1-7;312(5989):77-80 PMID: 6387509
  27. Complete sequence of the cDNA for human alpha 1-antitrypsin and the gene for the S variant.
    Biochemistry. 1984 Oct 9;23(21):4828-37 PMID: 6093867
  28. Improved resolution of PI (alpha 1-antitrypsin) phenotypes by a large-scale immobilized pH gradient.
    Am J Hum Genet. 1985 Sep;37(5):922-30 PMID: 3876767
  29. Evaluation of "at risk" alpha 1-antitrypsin genotype SZ with synthetic oligonucleotide gene probes.
    J Clin Invest. 1986 Feb;77(2):528-37 PMID: 3484754
  30. Regional location of alpha 1-antichymotrypsin and alpha 1-antitrypsin genes on human chromosome 14.
    Somat Cell Mol Genet. 1986 Mar;12(2):209-14 PMID: 3485824
  31. alpha 1-Antitrypsin Christchurch, 363 Glu----Lys: mutation at the P'5 position does not affect inhibitory activity.
    Biochim Biophys Acta. 1986 Sep 5;873(1):13-9 PMID: 3527273
  32. Identification of a second mutation in the protein-coding sequence of the Z type alpha 1-antitrypsin gene.
    J Biol Chem. 1986 Dec 5;261(34):15989-94 PMID: 3491072
  33. Replacement therapy for alpha 1-antitrypsin deficiency associated with emphysema.
    N Engl J Med. 1987 Apr 23;316(17):1055-62 PMID: 3494198
  34. alpha 1-Antitrypsin nullGranite Falls, a nonexpressing alpha 1-antitrypsin gene associated with a frameshift to stop mutation in a coding exon.
    J Biol Chem. 1987 Sep 5;262(25):11999-2004 PMID: 3040726
  35. Tissue-specific expression of the human alpha 1-antitrypsin gene is controlled by multiple cis-regulatory elements.
    Nucleic Acids Res. 1987 Oct 26;15(20):8399-415 PMID: 2823229
  36. Interaction of a liver-specific nuclear factor with the fibrinogen and alpha 1-antitrypsin promoters.
    Science. 1987 Oct 30;238(4827):688-92 PMID: 3499668
  37. Characterization of the M1(Ala213) type of alpha 1-antitrypsin, a newly recognized, common "normal" alpha 1-antitrypsin haplotype.
    Biochemistry. 1987 Aug 25;26(17):5259-67 PMID: 2890373
  38. Cis- and trans-acting elements responsible for the cell-specific expression of the human alpha 1-antitrypsin gene.
    EMBO J. 1987 Sep;6(9):2759-66 PMID: 2824193
  39. The human alpha 1-antitrypsin gene is transcribed from two different promoters in macrophages and hepatocytes.
    EMBO J. 1987 Sep;6(9):2767-71 PMID: 3500042
  40. Z-type alpha 1-antitrypsin is less competent than M1-type alpha 1-antitrypsin as an inhibitor of neutrophil elastase.
    J Clin Invest. 1987 Nov;80(5):1366-74 PMID: 3500183
  41. EK2 derivatives of bacteriophage lambda useful in the cloning of DNA from higher organisms: the lambdagtWES system.
    Science. 1977 Apr 8;196(4286):175-7 PMID: 322278
Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
0002-9297
Published
1988-09-00
Pages
322-30
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC1715372
Subset
IM
External Links
PubMed source PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2