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Thromb Haemost 1992; 68(04): 455-459
DOI: 10.1055/s-0038-1646296
Original Article
Schattauer GmbH Stuttgart

Two New Nonsense Mutations in Type Ia Antithrombin III Deficiency at Leu 140 and Arg 197

Akira Tomonari
The First Department of Internal Medicine, The University of Tokushima, Japan
,
Hiroyuki Iwahana
1   The Otsuka Department of Clinical and Molecular Nutrition, School of Medicine, The University of Tokushima, Japan
,
Katsuhiko Yoshimoto
1   The Otsuka Department of Clinical and Molecular Nutrition, School of Medicine, The University of Tokushima, Japan
,
Toshio Shigekiyo
The First Department of Internal Medicine, The University of Tokushima, Japan
,
Shiro Saito
The First Department of Internal Medicine, The University of Tokushima, Japan
,
Mitsuo Itakura
1   The Otsuka Department of Clinical and Molecular Nutrition, School of Medicine, The University of Tokushima, Japan
› Author Affiliations
Further Information

Publication History

Received 10 March 1992

Accepted after revision 20 May 1992

Publication Date:
04 July 2018 (online)

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Summary

Using polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and DNA sequencing, the molecular basis of hereditary type la antithrombin III (AT III) deficiency was disclosed in two families. One mutation was a change from T to A in the codon of TTA for Leu 140 forming a stop codon of TAA, which was confirmed by mutated primer-mediated PCR-HindIII digestion. The application of this method demonstrated that all four affected members had the mutant allele in a heterozygous state and that none of unaffected subjects had this mutation. Another mutation in the second family was a change from C to T in the codon of CGA for Arg 197 also forming a stop codon of TGA, which was confirmed by PCR-HaeIII digestion. Based on these, it was concluded that the two new nonsense mutations in the AT III gene in a heterozygous state are the molecular basis of hereditary type Ia AT III deficiency.

 

  • REFERENCES

  • 1 Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrh 1965; 13: 516-530
    PubMedGoogle Scholar
  • 2 Cosgriff TM, Bishop DT, Hershgorf EJ, Skolnick MH, Martin BA, Baty BJ, Carlson KS. Familial antithrombin III deficiency: Its natural history, genetics, diagnosis and treatment. Medicine 1983; 62: 209-220
    CrossrefPubMedGoogle Scholar
  • 3 Lane DA, Ireland H, Olds RJ, Thein SL, Perry DJ, Aiach M. Antithrombin III: A database of mutations. Thromb Haemostas 1991; 66: 657-661
    PubMedGoogle Scholar
  • 4 Bock SC, Wilon KL, Vehar GA, Lawn RM. Cloning and expression of the cDNA for human antithrombin III. Nucl Acids Res 1982; 10: 8113-8125
    CrossrefPubMedGoogle Scholar
  • 5 Bock SC, Harris JF, Balazs I, Trent JM. Assignment of the human antithrombin III structural gene to chromosome 1q23–25. Cytogenet Cell Genet 1985; 39: 67-69
    CrossrefPubMedGoogle Scholar
  • 6 Bock SC, Marrinan JA, Radziejewska E. Antithrombin III Utah: Proline-407 to leucine mutation in a highly conserved region near the inhibitor reactive site. Biochemistry 1988; 27: 6171-6178
    CrossrefPubMedGoogle Scholar
  • 7 Bock SC, Prochownik EV. Molecular genetic survey of 16 kindreds with hereditary antithrombin III deficiency. Blood 1987; 70: 1273-1278
    PubMedGoogle Scholar
  • 8 Olds RJ, Lane DA, Finazzi G, Barbui T, Thein SL. A frameshift mutation leading to type 1 antithrombin deficiency and thrombosis. Blood 1990; 76: 2182-2186
    PubMedGoogle Scholar
  • 9 Olds RJ, Lane DA, Ireland H, Leone G, DeStefano V, Cazenave JP, Wiesel ML, Thein SL. Novel point mutations leading to type Ia antithrombin deficiency and thrombosis. Br J Haematol 1991; 78: 408-413
    CrossrefPubMedGoogle Scholar
  • 10 Gandrille S, Vidaud D, Emmerich J, Clauser E, Sié P, Fiessinger JN, Alhenc-Gelas M, Priollet P, Aiach M. Molecular basis for hereditary antithrombin III quantitative deficiencies: a stop codon in exon IIIa and a frameshift in exon VI. Br J Haematol 1991; 78: 414-420
    CrossrefPubMedGoogle Scholar
  • 11 Grundy CB, Thomas F, Millar DS, Krawczak M, Melissari E, Lindo V, Moffat E, Kakkar VV, Cooper DN. Recurrent deletion in the human antithrombin III gene. Blood 1991; 78: 1027-1032
    PubMedGoogle Scholar
  • 12 Vidaud D, Emmerich J, Sirieix ME, Sié P, Alhenc-Gelas M, Aiach M. Molecular basis for antithrombin III type I deficiency: 3 novel mutations located in exon IV Blood. 1991; 78: 2305-2309
    PubMedGoogle Scholar
  • 13 Olds RJ, Lane DA, Ireland H, Finazzi G, Barbui T, Abildgaad U, Girolami A, Thein SL. A common point mutation producing type Ia antithrombin III deficiency. AT 129 CGA to TGA (Arg to stop). Thromb Res 1991; 64: 621-625
    CrossrefPubMedGoogle Scholar
  • 14 Uno Y, Shigekiyo T, Yoshimoto K, Saito S, Inomoto T. DNA analysis of antithrombin III (AT III) gene in three Japanese kindreds with congenital AT III deficiency. Jpn J Thromb Hemostas 1990; 1: 512-519
    PubMedGoogle Scholar
  • 15 Kusumi S, Kobayashi M, Takata N, Imanaka F, Maehama S, Taketomi Y, Fujimura K, Kuramoto A. Effect of AT III concentrate infusion therapy on the congenital AT III deficiency. Jpn J Clin Hematol 1984; 25: 25-30
    PubMedGoogle Scholar
  • 16 Kunkel LM, Smith KD, Boyer SH, Borgaonkar DS, Wachtel SS, Miller OJ, Breg WR, Jones HW, Rary JM. Analysis of human Y-chromosome-specific reiterated DNA in chromosome variants. Proc Natl Acad Sci USA 1977; 74: 5463-5467
    CrossrefPubMedGoogle Scholar
  • 17 Iwahana H, Yoshimoto K, Itakura M. Detection of point mutations by SSCP of PCR-amplified DNA after endonuclease digestion. Bio-techniques 1992; 12: 64-66
    PubMedGoogle Scholar
  • 18 Marchuk D, Drumm M, Saulimo A, Collins FS. Construction of T-vectors, a rapid and general system for direct cloning of unmodified PCR products. Nucl Acids Res 1991; 19: 1154
    CrossrefPubMedGoogle Scholar
  • 19 Schwartz EI, Shevtsov SP, Kuchinski AP, Kovalev YP, Plutalov OV, Berlin YA. Approach to identification of a point mutation in apoB100 gene by means of a PCR-mediated site-directed mutagenesis. Nucl Acids Res 1991; 19: 3752
    CrossrefPubMedGoogle Scholar
  • 20 Chandra T, Stackhouse R, Kidd VJ, Woo SLC. Isolation and sequence characterization of a cDNA clone of human antithrombin III. Proc Natl Acad Sci USA 1983; 80: 1845-1848
    CrossrefPubMedGoogle Scholar
  • 21 Winter JH, Bennett B, Watt JL, Brown T, Román CS, Schinzel A, King J, Cook JL. Confirmation of linkage between antithrombin III and Duffy blood group and assignment of AT3 to lq22–25. Ann Hum Genet 1982; 496: 29-34
    PubMedGoogle Scholar
  • 22 Orita M, Suzuki Y, Sekiya T, Hayashi K. Rapid and sensitive detection of point mutations and DNA polymorphisms using the polymerase chain reaction. Genomics 1989; 5: 874-879
    CrossrefPubMedGoogle Scholar
  • 23 Cooper DN, Krawczak M. Cytosine methylation and the fate of CpG dinucleotides in vertebrate genomes. Hum Genet 1989; 83: 182-188
    PubMedGoogle Scholar
  • 24 Steisinger G, Okada Y, Emrich J, Newton J, Tsugita A, Terzaghi E, Inouye M. Frameshift mutations and the genetic code. Cold Spring Harb Symp Quant Biol 1966; 31: 77-84
    CrossrefPubMedGoogle Scholar
  • 25 Bock SC, Sibermann JA, Wikoff W, Abildgaard U, Hultin MB. Identification of a threonine for alanine substitution at residue 404 of antithrombin III Oslo suggests integrity of the 404–407 region is important for maintaining normal plasma inhibitor levels. Thromb Haemostas 1989; 62: 494
    PubMedGoogle Scholar
  • 26 Nakagawa M, Tanaka S, Tsuji H, Takada O, Uno M, Hashimoto-Gotoh T, Wagatsuma M. Congenital antithrombin III deficiency (AT-III Kyoto): Identification of a point mutation altering arginine-406 to methionine behind the reactive site. Thromb Res 1991; 64: 101-108
    CrossrefPubMedGoogle Scholar
  • 27 Miura O, Aoki N. Impaired secretion of mutant α2-plasmin inhibitor (α2PI-Nara) from COS-7 and HepG2 cells: Molecular and cellular basis for hereditary deficiency of α2-plasmin inhibitor. Blood. 1990; 75: 1092-1096
    PubMedGoogle Scholar
  • 28 Satoh K, Nukiwa T, Brantly M, Garver Jr RI, Hofker M, Curtney M, Crystal RG. Emphysema associated with complete absence of α1-antitrypsin of a stop codon in an α1-antitrypsin-coding exon. Am J Hum Genet. 1988; 42: 77-83
    PubMedGoogle Scholar
  • 29 Curiel D, Brantly M, Curiel E, Stier L, Crystal RG. α1-antitrypsin deficiency caused by the α1-antitrypsin nullMattawa gene. An insertion mutation rendering the α1-antitrypsin gene incapable of producing α1-antitrypsin. J Clin Invest. 1989; 83: 1144-1152
    PubMedGoogle Scholar
  • 30 Takeshita K, Forget BG, Scarpa A, Benz Jr EJ. Intranuclear defect in β-globin mRNA accumulation due to a premature translation termination codon. Blood 1984; 64: 13-22
    PubMedGoogle Scholar