First Case of Sporadic Protein S Deficiency due to a Novel Candidate Mutation, Ala 484 → Pro, in the Protein S Active Gene (PROSl)

Summary

In a series of 16 propositi with symptomatic protein S deficiency and a protein S gene mutation, we identified a sporadic case of a novel mutation that probably affects gene expression. The mutation, a G to C transversion leading to the substitution of Ala 484 by Pro, was not found in the protein S gene of the patient’s parents. Transmission of the paternal and maternal protein S alleles was apparently normal, on the basis of the frequent polymorphism in exon XV. We also checked the transmission of chromosomal material by analysing protein C gene polymorphisms, Β-globin gene frameworks and four variable number of tandem repeats (VNTRs). By combining the results of these analyses, we were able to rule out nonpaternity and to confirm the de novo nature of the mutation.

• References

• 1 Ploos van Amstel HK, Reitsma PH. van der Logt PE, Bertina RM. Intronexon organization of the active human protein S gene PSa and its pseudogene PS (3: duplication and silencing during primate evolution. Biochemistry 1990; 29: 7853-7861
• 2 Schmidel DK, Tatro AV, Phelps LG, Tomczak JA, Long GL. Organization of the human protein S genes. Biochemistry 1990; 29: 7845-7852
• 3 Edenbrandt CM, 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
• 4 Ploos van Amstel JK, Van Der Zanden AL, Bakker E, Reitsma PH, Bertina RM. Two genes homologous with human protein S cDNA are located on chromosome 3. Thromb Haemost 1987; 58: 982
• 5 Dahlbäck B, Stenflo J. High molecular weight complex in human plasma between vitamin K-dependent protein S and complement C4b-binding protein. Proc Natl AcadSci USA 1981; 78: 2512-2516
• 6 Dahlbäck B. Purification of human C4b-binding protein and formation of its complex with vitamin K-dependent protein S. Biochem J 1983; 209: 847-856
• 7 Dahlbäck B. Inhibition of the protein Ca cofactor function of human and bovine protein S by C4b-binding protein. J Biol Chem 1986; 261: 12022-12027
• 8 Walker FJ. Regulation of activated protein C by protein S. The role of phospholipid in factor Va inactivation. J Biol Chem 1981; 256: 11128-11131
• 9 Koedam JA, Meijers JCM, Sixma JJ, Bouma BN. Inactivation of human factor VIII by activated protein C. Cofactor activity of protein S and protective effect of von Willebrand factor. J Clin Invest 1988; 82: 1236-1243
• 10 Suzuki K, Stenflo J, Dahlbäck B, Teodorsson B. Inactivation of human coagulation factor V by activated protein C. J Biol Chem 1983; 258: 1914-1920
• 11 Comp P, Esmon C. Recurrent venous thromboembolism in patients with a partial deficiency of protein S. N Engl J Med 1984; 311: 1525-1528
• 12 Schwartz H, Fischer M, Hopmeier P, Batard MA, Griffin JH. Familial protein S deficiency is associated with recurrent thrombosis. Blood 1984; 64: 1297-1300
• 13 Mahasandana C, Suvatte V, Chuansumrit A, Marlar RA, Manco-Johnson MJ, Jacobson LJ, Hathaway WE. Homozygous protein S deficiency in an infant with purpura fulminans. J Pediat 1990; 117: 750-753
• 14 Pegelow CH, Ledford M, Young J, Zilleruelo G. Severe protein S deficiency in a newborn. Pediatrics. 1992; 89: 674-676
• 15 Ploos van Amstel HK, Huisman MV, Reitsma PH, ten Cate JW, Bertina RM. Partial protein S gene deletion in a family with hereditary thrombophilia. Blood 1989; 73: 479-483
• 16 Schmidel DK, Nelson RM, Broxson Jr EH, Comp PC, Marlar RA, Long GL. A 5.3-kb deletion including exon XIII of the protein S a gene occurs in two protein S-deficient families. Blood 1991; 77: 551-559
• 17 Gomez E, Ledford MR, Pegelow CH, Reitsma PH, Bertina RM. Homozygous protein S deficiency due to a one base pair deletion that leads to a stop codon in exon III of the protein S gene. Thromb Haemost 1994; 71: 723-726
• 18 Reitsma PH, Ploos van Amstel HK, Bertina RM. Three novel mutations in five unrelated subjects with hereditary protein S deficiency type I. J Clin Invest 1994; 93: 486-492
• 19 Borgel D, Gandrille S, Gouault-Heilmann M, Aiach M. First frameshift mutation in the active protein S gene associated with a quantitative hereditary deficiency. Blood Coag Fibrinol 1994; 5: 593-600
• 20 Gandrille S, Borgel D, Eschwège-Gufflet V, Aillaud MF, Dreyfus M, Matheron C, Gaussem P, Abgrall JF, Jude B, Sie P, Toulon P, Aiach M. Identification of 15 different candidate causal point mutations and 3 polymorphisms in 19 patients with protein S deficiency using a scanning method for the analysis of the protein S active gene. Blood 1995; 85: 130-138
• 21 Gomez E, Poort SR, Bertina RM, Reitsma PH. Identification of eight point mutations in protein S deficiency type I - Analysis of 15 pedigrees. Thromb Haemost 1995; 73: 750-755
• 22 Yamazaki T, Hamaguchi M, Katsumi A, Kagami K, Kojima T, Takamatsu J, Saito H. A quantitative protein S deficiency associated with a novel nonsense mutation and markedly reduced levels of mutated mRNA. Thromb Haemost 1995; 74: 590-595
• 23 Formstone CJ, Wacey AI, Berg LP, Rahman S, Bevan D, Rowley M, Voke J, Bemardi F, Legnani C, Simioni P, Girolami A, Tuddenham EGD, Kakkar VV, Cooper DN. Detection and characterization of seven novel protein S (PROS) gene lesions: Evaluation of reverse transcript-polymerase chain reaction as a mutation screening strategy. Blood 1995; 86: 2632-2641
• 24 Mustafa S, Pabinger I, Mannhalter C. Protein S deficiency type I: Identification of point mutations in 9 of 10 families. Blood 1995; 86: 3444-3451
• 2 Comp PC. Laboratory evaluation of protein S status. Semin Thromb Hemost 1990; 16: 177-181
• 26 Gyllensten UB, Erlich HA. Generation of single-stranded DNA by the polymerase chain reaction and its application to direct sequencing of the HLA-DQA locus. Proc Natl Acad Sci USA 1988; 85: 7652-7656
• 27 Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 1977; 74: 5463-5467
• 28 Gandrille S, Aiach M. Polymorphism in the protein C gene detected by denaturing gradient gel electrophoresis. Nucl Acid Res 1991; 19: 6982
• 29 Reitsma PH, Poort SR, Allaart CF, Briët E, Bertina RM. The spectrum of genetic defects in a panel of 40 Dutch families with symptomatic protein C deficiency type I: heterogeneity and founder effects. Blood 1991; 78: 890-894
• 30 Spek CA, Poort SR, Bertina RM, Reitsma PH. Determination of the allelic and haplotype frequencies of three polymorphisms in the promotor region of the human protein C gene. Blood Coag Fibrinol 1994; 5: 309-311
• 31 Gandrille S, Goossens M, Aiach M. Scanning method to establish the molecular basis of protein C deficiencies. Hum Mut 1994; 4: 20-30
• 32 Foster DC, Yoshitake S, Davie EW. The nucleotide sequence of the gene for human protein C. Proc Natl Acad Sci USA 1985; 82: 4673-4677
• 33 Gandrille S, Jude B, Alhenc-Gelas M, Emmerich J, Aiach M. First de novo mutations in the protein C gene of two patients with type I deficiency: a missense mutation and a splice site deletion. Blood 1994; 84: 2566-2570
• 34 Ghanem N, Girodon E, Vidaud M, Martin J, Fanen P, Plassa F, Goossens M. A comprehensive scanning method for rapid detection of Β-globin gene mutations and polymorphisms. Hum Mut 1992; 1: 229-239
• 35 Budowle B, Chakrabarty R, Giusti AM, Eisenberg AJ, Allen RC. Analysis of the VNTR locus D1S80 by the PCR followed by high-resolution PAGE. Am J Hum Genet 1991; 48: 137-144
• 36 Horn GT, Richards B, Klinger KW. Amplification of a highly polymorphic VNTR segment by the polymerase chain reaction. Nucl Acid Res 1989; 17: 2140
• 37 Odelberg SJ, Plaetke R, Eldridge JR, Ballard L, O’Connell P, Nakamura Y, Leppert M, Lalouel JM, White R. Characterization of eight VNTR loci by agarose gel electrophoresis. Genomics 1989; 5: 915-924
• 38 Ludwig EH, Friedl W, McCarthy BJ. High-resolution analysis of a hypervariable region in the human apolipoprotein B gene. Am J Hum Genet 1989; 45: 458-464
• 39 Boerwinkle E, Xiong W, Fourest E, Chan L. Rapid typing of tandemly repeated hypervariable loci by the polymerase chain reaction: Application to the apolipoprotein B ’ hypervariable region. Proc Natl Acad Sci USA 1989; 86: 212-216
• 40 Peake IR, Bowen D, Bignell P, Liddell MB, Sadler JE, Standen G, Bloom AL. Family studies and prenatal diagnosis in severe von Willebrand disease by polymerase chain reaction amplification of a variable number tandem repeat region of the von Willebrand factor gene. Blood 1990; 76: 555-561
• 41 Standen GR, Bignell P, Bowen DJ, Peake IR, Bloom AL. Family studies in von Willebrand’s disease by analysis of restriction fragment length polymorphisms and an intragenic variable number tandem repeat (VNTR) sequence. Br J Haematol 1990; 76: 242-249
• 42 Diepstraten CM, Ploos van Amstel JK, Reitsma PH, Bertina RM. A CCA/CCG neutral polymorphism in the codon for Pro 626 of the human protein S gene PS alpha (PROS1). Nucl Acid Res 1991; 19: 5091
• 43 Grompe M. The rapid detection of unknown mutations in nucleic acids. Nature Genetics 1993; 5: 111-117
• 44 Hoskins JA, Norman DK, Beckmann RJ, Long GL. Cloning and characterization of human liver cDNA encoding a protein S precursor. Proc Natl Acad Sci USA 1987; 84: 349-353
• 45 Dahlbäck B, Lundwall A, Stenflo J. Primary structure of bovine vitamin K-dependent protein S. Proc Natl Acad Sci USA 1986; 83: 4199-4203
• 46 Chu MD, 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
• 47 Yasuda F, Hayashi T, Tanitame K, Nishioka J, Suzuki K. Molecular cloning and functional characterization of rat plasma protein S. J Biochem 1995; 117: 374-383
• 48 Greengard JS, Fernandez JA, Radkte KP, Griffin JH. Identification of candidate residues for interaction of protein S with C4b binding protein and activated protein C. Biochem J 1995; 305: 397-403
• 49 Giannelli F, Green PM, High KA, Sommer S, Poon MC, Ludwig M, Schwaab R, Reitsma PH, Goossens M, Yoshioka A, Brownlee GG. Haemophilia B: Database of point mutations and short additions and deletions-fourth edition, 1993. Nucl Acid Res 1993; 21: 3075-3087
• 50 Reitsma PH, Bemardi F, Doig RG, Gandrille S, Greengard JS, Ireland H, Krawczak M, Lind B, Long GL, Poort SR, Saito H, Sala N, Witt I, Cooper DN. Protein C deficiency: A database of mutations, 1995 update. Thromb Haemost 1995; 73: 876-889
• 51 Haldane JBS. The rate of spontaneous mutation of a human gene. J Genet 1935; 31: 317-326