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Thromb Haemost 1998; 79(06): 1086-1091
DOI: 10.1055/s-0037-1615020
DOI: 10.1055/s-0037-1615020
Rapid Communication
A Novel Mutation in Intron K of the PROS1 Gene Causes Aberrant RNA Splicing and Is a Common Cause of Protein S Deficiency in a UK Thrombophilia Cohort
Supported by a grant from the British Heart Foundation.
Further Information
Publication History
Received
10 October 1997
Accepted after resubmission
04 February 1998
Publication Date:
07 December 2017 (online)
Summary
In the course of investigating the molecular basis of protein S deficiency in 31 index cases with thrombophilia, we identified seven kindred where the underlying defect was a novel A to G transition 9 bp upstream of exon 12 in intron K of the PROS1 gene. In all but one case, the mutation caused type I deficiency. One individual had type III deficiency. While ectopic transcript analysis using the BstXI dimorphism in exon 15 failed to detect a transcript from the mutated allele, analysis of transcripts spanning exons 11 and 12 revealed a minor mRNA species. Sequencing confirmed the mutation created a new RNA acceptor site introducing 8 nucleotides of intronic sequence into the mature mRNA. Haplotype analysis of the defective PROS1 alleles in six families revealed the same haplotype in all affected individuals suggesting the presence of a common ancestor. Six of the fourteen relatives with the mutation experienced at least one venous thrombotic event strongly supporting the association of the mutation with venous thrombosis.
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References
- 1 Esmon CT. The regulation of natural anticoagulant pathways.. Science 1987; 235: 1348-52.
- 2 Lundwall A, Dackowski W, Cohen E, Shaffer M, Mahr A, Dahlbäck B, Stenflo J, Wydro R. Isolation and sequence of the cDNA for human protein S, a regulator of blood coagulation.. Proc Natl Acad Sci USA 1986; 83: 6716-20.
- 3 Dahlbäck B, Stenflo J. High molecular weight complex in human plasma between vitamin K-dependent protein S and complement component C4b-binding protein.. Proc Natl Acad Sci USA 1981; 78: 2512-6.
- 4 Dahlbäck B. Inhibition of protein C cofactor function of human and bovine protein S by C4b-binding protein.. J Biol Chem 1986; 261: 2022-7.
- 5 Comp PC, Nixon RR, Cooper MR, Esmon CT. Familial protein S deficiency is associated with recurrent thrombosis.. J Clin Invest 1984; 74: 2082-8.
- 6 Lane DA, Mannucci PM, Bauer KA, Bertina RM, Bochkov NP, Boulyjenkov V, Chandy M, Dahlbäck B, Ginter EK, Miletich JP, Rosendaal FR, Seligsohn U. Inherited Thrombophilia: Part 1.. Thromb Haemost 1996; 76: 651-62.
- 7 Watkins PC, Eddy R, Fukushima Y, Byers MG, Cohen EH, Dackowski WR, Wydro RM, Shows TB. The gene for protein S maps near the centromere of human chromosome 3.. Blood 1988; 71: 238-41.
- 8 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: 982-7.
- 9 Schmidel DK, Tatro AV, Phelps LG, Tomczak JA, Long GL. Organization of the human protein S genes.. Biochemistry 1990; 29: 7845-52.
- 10 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: 7861-8.
- 11 Diepstraten CM, Ploos van Amstel JK, Reistma PH, Bertina RA. A CCA/CCG neutral dimorphism in the codon for Pro626 of the human protein S gene PSα (PROS1).. Nucleic Acid Res 1991; 19: 5091.
- 12 Sacchi E, Pinotti M, Marchetti G, Merati G, Tagliabue L, Mannucci PM, Bernardi F. Protein S mRNA in patients with protein S deficiency.. Thromb Haemost 1995; 73: 746-9.
- 13 Mustafa S, Pabinger I, Mannhalter C. Two new frequent dimorphisms in the protein S (PROS1) gene.. Thromb Haemost 1996; 76: 393-6.
- 14 Gandrille S, Borgel D, Ireland H, Lane DA, Simmonds R, Reitsma PH, Mannhalter C, Pabinger I, Saito H, Suzuki K, Formstone C, Cooper DN, Espinosa Y, Sala N, Bernardi F, Aiach M. Protein S Deficiency: A Database of Mutations.. Thromb Haemost 1997; 77: 1201-4.
- 15 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: 486-92.
- 16 Gómez 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: 750-5.
- 17 Duchemin J, Borg J-Y, Borgel D, Vasse M, Lévèque H, Aiach M, Gandrille S. Five novel mutations of the protein S active gene (PROS1) in 8 Norman families.. Thromb Haemost 1996; 75: 437-44.
- 18 Beauchamp NJ, Daly M, Cooper PC, Makris M, Preston E, Peake IR. Molecular basis of protein S deficiency in three families also showing independent inheritance of factor V Leiden.. Blood 1996; 88: 1700-7.
- 19 Beauchamp NJ, Daly ME, Hampton KK, Cooper PC, Preston FE, Peake IR. High prevalence of a mutation in the factor V gene within the UK population: Relationship to activated protein C resistance and familial thrombosis.. Br J Haematol 1994; 88: 219-22.
- 20 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3’-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.. Blood 1996; 8: 3698-703.
- 21 Ganguly A, Rock MJ, Prockop DJ. Conformation-sensitive gel electrophoresis for rapid detection of single-base differences in double-stranded PCR products and DNA fragments: Evidence for solvent-induced bends in DNA heteroduplexes.. Proc Natl Acad Sci USA 1993; 90: 10325-9.
- 22 Williams IJ, Abuzenadah A, Winship PR, Preston FE, Dolan G, Wright J, Peake IR, Goodeve AC. Precise carrier diagnosis in families with haemophilia A: Use of conformation sensitive gel electrophoresis for mutation screening and polymorphism analysis.. Thromb Haemost 1998; 79: 723-6.
- 23 Cooper DN, Krawczak M. In: Human gene mutation.. BIOS Scientific Publishers Ltd; Oxford: 1993
- 24 Mustafa S, Pabinger I, Mannhalter C. Protein S deficiency type I: Identification of point mutations in 9 of 10 families.. Blood 1995; 86: 3444-51.
- 25 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: 590-5.
- 26 Bustorff TC, Freire I, Gago T, Crespo F, David D. Identification of three novel mutations in hereditary protein S deficiency.. Thromb Haemost 1997; 77: 21-5.