Semin Thromb Hemost 2001; 27(2): 155-160
DOI: 10.1055/s-2001-14075
Copyright © 2001 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

DNA Sequence Analysis of Protein S Deficiency-Identification of Four Point Mutations in Twelve Japanese Subjects

Takayuki Iwaki1 , Tadashi Mastushita2 , Takao Kobayashi1 , Yukako Yamamoto3 , Yuka Nomura2 , Kazuo Kagami2 , Takayuki Nakayama2 , Isamu Sugiura4 , Tetsuhito Kojima5 , Junki Takamatsu3 , Naohiro Kanayama1 , Hidehiko Saito2 6
  • 1Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, Hamamatsu, Japan
  • 2First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya, Japan
  • 3Department of Transfusion Medicine, Nagoya University Hospital, Nagoya, Japan
  • 4Toyohashi City Hospital, Toyohashi, Japan
  • 5Department of Medical Technology, Nagoya University School of Health Sciences, Nagoya, Japan
  • 6Aichi Blood Disease Research Foundation, Nagoya, Japan
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
31. Dezember 2001 (online)

ABSTRACT

The molecular basis for the hereditary type I protein S (PS) deficiency was investigated. DNA sequence analysis of 12 patients with PS deficiency in Japan identified four point mutations and three of them were novel. Nonsense mutations found in two unrelated patients resulted in termination of the PS polypeptide chains at Gln 238 and Lys 392, respectively. Two novel missense mutations were also found in two other patients substituting Asp 202 for Asn and Leu 298 for Pro, respectively. Comparison of the PS amino acid sequences from several mammalians indicated that Asp 202 and Leu 298 were preserved and thus appeared to be responsible for the pathogenesis of PS deficiency.

REFERENCES

  • 1 Esmon C T. The protein C anticoagulant pathway.  Arterioscler Thromb . 1992;  12 135-145
  • 2 Dahlbäck B. Protein S and C4b-binding protein: components involved in the regulation of the protein C anticoagulant system.  Thromb Haemost . 1991;  66 49-61
  • 3 Comp P C, Esmon C T. Recurrent venous thromboembolism in patients with a partial deficiency of protein S.  N Engl J Med . 1984;  311 1525-1528
  • 4 Comp P C, Nixon R R, Cooper M R, Esmon C T. Familial protein S deficiency is associated with recurrent thrombosis.  J Clin Invest . 1984;  74 2082-2088
  • 5 Kamiya T, Sugihara T, Ogata K,. Inherited deficiency of protein S in a Japanese family with recurrent venous thrombosis: a study of three generations.  Blood . 1986;  67 406-410
  • 6 Zoller B, Garcia de Frutos P, Dahlbäck B. Evaluation of the relationship between protein S and C4b-binding protein isoforms in hereditary protein S deficiency demonstrating type I and type III deficiencies to be phenotypic variants of the same genetic disease.  Blood . 1995;  85 3524-3531
  • 7 Schmidel D K, Tatro A V, Phelps L G, Tomczak J A, Long G L. Organization of the human protein S genes.  Biochemistry . 1990;  29 7845-7852
  • 8 Gandrille S, Borgel D, Ireland H. Protein S deficiency: a database of mutations. For the plasma coagulation inhibitors subcommittee of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis.  Thromb Haemost . 1997;  77 1201-1214
  • 9 Yamazaki T, Katsumi A, Okamoto Y. Two distinct novel splice site mutations in a compound heterozygous patient with protein S deficiency.  Thromb Haemost . 1997;  77 14-20
  • 10 Okamoto Y, Yamazaki T, Katsumi A. A novel nonsense mutation associated with an exon skipping in a patient with hereditary protein S deficiency type I.  Thromb Haemost . 1996;  75 877-882
  • 11 Yamazaki T, Katsumi A, Kagami K. Molecular basis of a hereditary type I protein S deficiency caused by a substitution of Cys for Arg474.  Blood . 1996;  87 4643-4650
  • 12 Yamazaki T, Hamaguchi M, Katsumi A. A quantitative protein S deficiency associated with a novel nonsense mutation and markedly reduced levels of mutated mRNA.  Thromb Haemost . 1995;  74 590-595
  • 13 Yamazaki T, Sugiura I, Matsushita T. A phenotypically neutral dimorphism of protein S: the substitution of Lys155 by Glu in the second EGF domain predicted by an A to G base exchange in the gene.  Thromb Res . 1993;  70 395-403
  • 14 Tanimoto M, Kojima T, Kamiya T. DNA analysis of seven patients with hemophilia B who have anti-factor IX antibodies: relationship to clinical manifestations and evidence that the abnormal gene was inherited.  J Lab Clin Med . 1988;  112 307-313
  • 15 Schmidel D K, Tatro A V, Phelps L G, Tomczak J A, Long G L. Organization of the human protein S genes.  Biochemistry . 1990;  29 7845-7852
  • 16 Espinosa-Parrilla Y, Morell M, Souto J C. Protein S gene analysis reveals the presence of a cosegregating mutation in most pedigrees with type I but not type III PS deficiency.  Hum Mutat . 1999;  14 30-39
  • 17 Dahlbäck B, Lundwall A, Stenflo J. Primary structure of bovine vitamin K-dependent protein S.  Proc Natl Acad Sci USA . 1986;  83 4199-4203
  • 18 Chu M D, Sun J, Bird P. Cloning and sequencing of a cDNA encoding the murine vitamin K-dependent protein S.  Biochim Biophys Acta . 1994;  1217 325-328
  • 19 He X, Dahlbäck B. Molecular cloning, expression and functional characterization of rabbit anticoagulant vitamin-K- dependent protein S.  Eur J Biochem . 1993;  217 857-865
  • 20 Greengard J S, Fernandez J A, Radtke K P, Griffin J H. Identification of candidate residues for interaction of protein S with C4b binding protein and activated protein C.  Biochem J . 1995;  305 397-403
  • 21 Reitsma P H, Ploos van Amstel K H, Bertina R M. Three novel mutations in five unrelated subjects with hereditary protein S deficiency type I.  J Clin Invest . 1994;  93 486-492
  • 22 Borgel D, Duchemin J, Alhenc-Gelas M. Molecular basis for protein S hereditary deficiency: genetic defects observed in 118 patients with type I and type IIa deficiencies. The French network on molecular abnormalities responsible for protein C and protein S deficiencies.  J Lab Clin Med . 1996;  128 218-227
  • 23 Gomez E, Poort S R, Bertina R M, Reitsma P H. Identification of eight point mutations in protein S deficiency type I-analysis of 15 pedigrees.  Thromb Haemost . 1995;  73 750-755
  • 24 Poort S R, Pabinger-Fasching I, Mannhalter C, Reitsma P H, Bertina R M. Twelve novel and two recurrent mutations in 14 Austrian families with hereditary protein C deficiency.  Blood Coagul Fibrinolysis . 1993;  4 273-280
  • 25 Alhenc-Gelas M, Gandrille S, Aubry M L, Aiach M. Thirty-three novel mutations in the protein C gene. French inserm network on molecular abnormalities responsible for protein C and protein S.  Thromb Haemost . 2000;  83 86-92
  • 26 Schmidel D K, Nelson R M, Broxson Jr H E. A 5.3-kb deletion including exon XIII of the protein S alpha gene occurs in two protein S-deficient families.  Blood . 1991;  77 551-559
  • 27 Ploos van Amstel K H, Huisman M V, Reitsma P H, Wouter ten Cate J, Bertina R M. Partial protein S gene deletion in a family with hereditary thrombophilia.  Blood . 1989;  73 479-483
  • 28 Matsuda M, Sugo T, Sakata Y. A thrombotic state due to an abnormal protein C.  N Engl J Med . 1988;  319 1265-1268
  • 29 Kemball-Cook G, Tuddenham E GD, Wacey A I. The factor VIII structure and mutation resource site: hamsters version 4.  Nucleic Acids Res . 1998;  26 216-219
  • 30 Saad S, Rowley G, Tagliavacca L, Green P M, Giannelli F. First report on UK database of haemophilia B mutations and pedigrees. UK haemophilia centres.  Thromb Haemost . 1994;  71 563-570
  • 31 Edenbrandt C M, Lundwall A, Wydro R, Stenflo J. Molecular analysis of the gene for vitamin K dependent protein S and its pseudogene. Cloning and partial gene organization.  Biochemistry . 1990;  29 7861-7868
  • 32 Ploos van Amstel K H, Reitsma P H, van der Logt P C, Bertina R M. Intron-exon organization of the active human protein S gene PS alpha and its pseudogene PS beta: duplication and silencing during primate evolution.  Biochemistry . 1990;  29 7853-7861
  • 33 Harada F, Kimura A, Iwanaga T. Gene conversion-like events cause steroid 21-hydroxylase deficiency in congenital adrenal hyperplasia.  Proc Natl Acad Sci USA . 1987;  84 8091-8094
  • 34 Lakich D, Kazazian Jr H H, Antonarakis S E, Gitschier J. Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A.  Nat Genet . 1993;  5 236-241