Summary
The most common deficiency allele of the protease inhibitor (PI) α1 (α1AT) is PI*Z. Other rare deficiency alleles of α1AT are of two types: those producing low but detectable amounts of α1AT (<20% of normal serum concentrations), and null alleles producing <1% of normal α1AT and therefore not detectable by routine quantitative methods. We have previously used DNA polymorphisms and family data to determine heterozygosity in an individual producing low levels of serum α1AT (12% of normal) of PI type Mmalton. By DNA analysis we observed the typical haplotype associated with PI* Mmalton and a unique null haplotype associated with the allele PI*QObolton. The QObolton allele produces no detectable serum α1AT. We have cloned and sequenced the QObolton allele from a phage genomic library. Deletion of a single cytosine residue near the active site of α1AT in exon V results in a frameshift causing an in-frame stop codon downstream of the deletion. This stop codon leads to premature termination of protein translation at amino acid 373, resulting in a truncated protein. The truncated protein is predicted to have an altered carboxy terminus (amino acids 363-) and will lack structurally important amino acids.
Similar content being viewed by others
References
Arnaud P, Wilson GB, Koistinen J, Fudenburg HH (1977) Immunofixation after electrofocusing: improved method for specific detection of serum proteins with determination of isoelectric points. I. Immunofixation print technique for detection of alpha1-protease inhibitor. J Immunol Methods 16:221–231
Bao J-J, Fourquet LR, Sifers RN, Kidd VJ, Woo SLC (1988) Molecular structure and sequence homology of a gene related to α1-antitrypsin in the human genome. Genomics 2:165–173
Brantly M, Paul L, Straus S, Dalgleish R, Courtney M, Tolstoshev P, LeCocq JP, Crystal M (1984) Heterogeneity of α1-antitrypsin gene sequences among individuals with the M phenotype. Clin Res 32:288A
Brantly M, Nukiwa T, Crystal RG (1988) Molecular basis of α1-antitrypsin deficiency. Am J Med 84:13–31
Carlson J, Stenflo J (1981) Rat α1-antitrypsin: preliminary characterization of the in vitro mRNA translation product. FEBS Lett 130: 297–300
Carrell RW, Jeppsson J-O, Laurell C-B, Brennan SO, Owen MC, Vaughan L, Boswell DR (1982) Structure and variation of human α1-antitrypsin. Nature 298:329–334
Ciliberto G, Dente L, Cortese R (1985) Cell-specific expression of a transfected human α1-antitrypsin gene. Cell 41:531–540
Cox DW (1976) A new deficiency allele of alpha1-antitrypsin: Pi Mmalton. In: Peters H (ed) Protides of the biological fluids, vol 23. Pergamon Press, Oxford, pp 375–378
Cox DW (1981) New variants of α1-antitrypsin: comparison of Pi typing techniques. Am J Hum Genet 33:354–365
Cox DW (1989) Alpha1-antitrypsin deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease, 6th edn. McGraw-Hill, New York, pp 2409–2437
Cox DW, Billingsley GD (1989) Rare deficiency types of α1-antitrypsin: electrophoretic variation and DNA haplotypes. Am J Hum Genet 44:844–854
Cox DW, Coulson SE (1987) BglII polymorphism for the α1-antitrypsin related gene on chromosome 14. Nucleic Acids Res 15:4701
Cox DW, Levison H (1988) Emphysema of early onset associated with a complete deficiency of alpha1-antitrypsin (null hemozygotes). Am Rev Respir Dis 137:371–375
Cox DW, Johnson AM, Fagerhol MK (1980) Report of nomenclature meeting for α1-antitrypsin. INSERM Rouen/Bois-Guillaume 1978. Hum Genet 53:429–433
Cox DW, Billingsley GD, Smyth S (1981) Rare types of α1-antitrypsin associated with deficiency. In: Allen RC, Arnaud P (eds) Electrophoresis: Proceedings of the 3rd International Conference on Electrophoresis. de Gruyter, New York Berlin, pp 505–510
Cox DW, Woo SLC, Mansfield T (1985) DNA restriction fragments associated with alpha1-antitrypsin indicate a single origin for deficiency allele PIZ. Nature 316:79–81
Cox DW, Billingsley GD, Callaban JW (1986) Aggregation of plasma Z type α-antitrypsin suggests basic defect for the deficiency. FEBS Lett 205:255–260
Cox DW, Billingsley GD, Mansfield T (1987) DNA restriction site polymorphisms associated with the alpha1-antitrypsin gene. Am J Hum Genet 41: 891–906
Curiel D, Brantly M, Curiel E, Stier L, Crystal R (1989) α-Antitrypsin deficiency caused by α1-antitrypsin null mattawa gene: an insertion mutation rendering the α1-antitrypsin gene incapable of producing α1-antitrypsin. J Clin Invest 83:1144–1152
Eriksson S, Hagerstrand I (1974) Cirrhosis and malignant hepatoma in α1-antitrypsin deficiency. Acta Med Scand 195:451–458
Fagerhol MK (1968) The Pi-system. Ser Haematol 1:153–161
Fagerhol MK, Cox DW (1981) The Pi polymorphism: genetic, biochemical and clinical aspects of human α1-antitrypsin. In: Harris H, Hirschhorn K (eds) Advances in human genetics, vol 11. Plenum Press, New York London, pp 21–62
Fraizer GC, Harrold TR, Hofker MH, Cox DW (1989) In-frame single codon deletion in the Mmalton deficiency allele of α1-antitrypsin. Am J Hum Genet 44:894–902
Hodgson I, Kalsheker N (1987) DNA polymorphisms of the human α1-antitrypsin gene in normal subjects and in patients with pulmonary emphysema. J Med Genet 24:47–51
Hofker MH, Nelen M, Klasen EC, Nukiwa T, Crystal RG, Frants RR (1988) Cloning and characterization of an α1-antitrypsin like (PIL) gene 12 kb downstream of the genuine PI gene. Biochem Biophys Res Commun 155:634–642
Hofker MH, Nukiwa T, Paassen HMB van, Nelen M, Frants RR, Kramps JA, Klasen EC, Crystal RG (1989) A pro→leu substitution in codon 369 in the α1-antitrypsin deficiency variant PI Mheerlen. Hum Genet 81:264–268
Kalsheker NA, Hodgson IJ, Watkins GL, White J, Morrison MM, Stockely RA (1987) Deoxyribonucleic acid (DNA) polymorphism of the α1-antitrypsin gene in chronic lung disease. Br Med J 294:1511–1514
Kidd VJ, Wallace R, Itakura K, Woo SLC (1983) 382-17 deficiency detection by direct analysis of the mutation in the gene. Nature 304:230–234
Kramps JA, Brouwers JW, Maesen F, Dijkman JH (1981) PiMheerlen, a PiM allele resulting in very low α1-antitrypsin serum levels. Hum Genet 59:104–107
Laurell C-B, Eriksson S (1963) The electrophoretic α1-globulin pattern of serum in α1-antitrypsin deficiency. Scand J Clin Lab Invest 15:132–140
Lieberman J, Gaidulis L, Klotz SD (1976) A new deficient variant of α1-antitrypsin (MDuarte). Inability to detect the heterozygous state by antitrypsin phenotyping. Am Rev Respir Dis 113:31–36
Loebermann H, Tokuoka R, Deisenhofer J, Huber R (1984) Human α1-proteinase inhibitor. Crystal structure analysis of two crystal modifications, molecular model and preliminary analysis of the implications for function. J Mol Biol 177:531–557
Long GL, Chandra T, Woo SLC, Davie EW, Kurachi K (1984) Complete sequence of the cDNA for human α1-antitrypsin and the gene for the S variant. Biochemistry 23:4828–4837
Madisen L, Hoar DI, Holyrod CD, Crisp M, Hodes ME (1987) DNA banking: the effects of storage of blood and isolated DNA on the integrity of DNA. Am J Med Genet 27:379–390
Maniatis T, Fritsch EF, Sambrook J (eds) (1982) Molecular cloning: a laboratory manual. Cold Spring Harbor Laboratory, Cold Spring Habor, NY
Martin J-P, Sesboue R, Charlionet R, Ropartz C (1975) Does alpha1-antitrypsin PI null phenotype exist? Humangenetik 30:121–125
Nukiwa T, Satoh K, Brantly M, Ogushi F, Fells GA, Courtney M, Crystal RG (1986) Identification of a second mutation in the protein coding sequence of the Z-type α1-antitrypsin gene. J Biol Chem 261:15989–15994
Nukiwa T, Takahashi H, Brantly M, Courtney M, Crystal RG (1987) 382-25 nullGranite Falls, a nonexpressing 382-26 gene associated with a frameshift to stop mutation in a coding exon. J Biol Chem 262:11999–12004
Perlino E, Cortese R, Ciliberto G (1987) The human α1-antitrypsin gene is transcribed from two different promoters in macrophages and hepatocytes. EMBO J 6:2767–2771
Satoh K, Nukiwa T, Brantly M, Garver Jr RI, Hofker M, Courtney M, Crystal RG (1988) Emphysema associated with complete absence of α1-antitrypsin in serum and the homozygous inheritance of a stop codon in an α1-antitrypsin-coding exon. Am J Hum Genet 42:77–83
Saiki RK, Gelfand D, Stoffel S, Scharf S, Higuchi R, Horn G, Mullis K, Ehrlich H (1988) Primer directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 239:487–494
Sharp HL (1971) Alpha1-antitrypsin deficiency. Hosp Pract 5:83–96
Sharp HL, Bridges RA, Krivit W, Freier EF (1969) Cirrhosis associated with alpha1-antitrypsin deficiency: a previously unrecognized inherited disorder. J Lab Clin Med 73:934–939
Sifers RN, Brashears-Macatee S, Kidd VJ, Muensch H, Woo SLC (1988) A frameshift mutation results in a truncated α1-antitrypsin that is retained within the rough endoplasmic reticulum. J Biol Chem 263:7330–7335
Takahashi H, Nukiwa T, Satoh K, Ogushi F, Brantly M, Fells G, Stier L, Courtney M, Crystal RG (1988) Characterization of the gene and protein of the α1-antitrypsin “deficiency” allele Mprocida. J Biol Chem 263:15528–15534
Travis J, Salvesen GS (1983) Human plasma proteinase inhibitors. Annu Rev Biochem 52:655–709
Wewers MD, Casolaro MA, Crystal RC (1987) Comparison of alpha1-antitrypsin levels and antineutrophil elastase capacity of blood and lung in a patient with the alpha1-antitrypsin phenotype null-null before and during alpha1-anitrypsin augmentation therapy. Am Rev Respir Dis 135:539–543
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Fraizer, G.C., Siewertsen, M., Harrold, T.R. et al. Deletion/frameshift mutation in the α1 null allele, PI*QObolton . Hum Genet 83, 377–382 (1989). https://doi.org/10.1007/BF00291385
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF00291385