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DOI: 10.1160/TH12-01-0040
Small and large PROS1 deletions but no other types of rearrangements detected in patients with protein S deficiency
Publication History
Received:
23 January 2012
Accepted after major revision:
19 April 2012
Publication Date:
22 November 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/201201/lookinside/thumbnails/10-1160-th12-01-0040-1.jpg)
Summary
Protein S deficiency is a dominantly inherited disorder that results from mutations in the PROS1 gene. Previous sequencing of the gene failed to detect mutations in eight out of 18 investigated Swedish families, whereas segregation analyses detected large deletions in three out of the eight families. The present study investigates more thoroughly for the presence of deletions but also for other types of rearrangements. FISH analysis confirmed the existence of the three previously identified large deletions, but failed to identify any other type of rearrangement among the eight analysed families. MLPA analysis of the PROS1 gene revealed two smaller deletions covering two and four exons, respectively. Thus, deletions could be found in five out of eight families where no point mutations could be found despite sequencing of the gene. Twelve additional, not previously analysed, families were subsequently analysed using MLPA. The analysis identified two smaller deletions (3 and 4 exons). Including all PS-deficient families, i.e. also the 10 families where sequencing found a causative point mutation, deletions were identified in seven out of 30 PS-deficient families. A strategy of sequencing followed by MLPA analysis in mutation-negative families identified the causative mutation in 15 out of 18 of Swedish PS-deficient families. Most deletions were different as determined by their sizes, locations and flanking haplotypes. FISH (8 families) and MLPA analysis (20 families) failed to identify other types of rearrangements.
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References
- 1 Dahlbäck B. Blood coagulation. Lancet 2000; 355: 1627-1632.
- 2 Comp PC, Nixon RR, Cooper MR. et al. Familial protein S deficiency is associated with recurrent thrombosis. J Clin Invest 1984; 74: 2082-2088.
- 3 Comp PC, Esmon CT. Recurrent thromboembolism in patients with a partial deficiency of protein S. N Eng J Med 1984; 311: 1525-1528.
- 4 Schwarz H P, Fischer M, Hopmeier P. et al. Plasma protein S deficiency in familial thrombotic disease. Blood 1984; 64: 1297-1300.
- 5 Watkins PC, Eddy R, Fukushima Y. et al. The gene for protein S maps near the centromere of human chromosome 3. Blood 1988; 71: 238-241.
- 6 Edenbrandt CM, Lundwall Å, Wydro R. et al. Molecular analysis of the gene for vitamin K dependent protein S and its pseudogene. Cloning and partial gene organization. Biochemistry 1990; 29: 7861-7868.
- 7 Ploos van Amstel HK, Reitsma PH, van der Logt CPE. et al. 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.
- 8 Schmidel DK, Tatro AV, Phelps LG. et al. Organization of the human protein S genes. Biochemistry 1990; 29: 7845-7852.
- 9 Persson KEM, Dahlbäck B, Hillarp A. Diagnosing protein S deficiency: Analytical considerations. Clin Lab 2003; 49: 103-110.
- 10 Lane DA, Mannucci PM, Bauer KA. et al. Inherited thrombophilia: Part 1. Thromb Haemost 1996; 76: 651-662.
- 11 Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Eng J Med 2001; 344: 1222-1231.
- 12 Dykes AC, Walker ID, McMahon AD. et al. A study of protein S antigen levels in 3788 healthy volunteers: influence of age, sex and hormone use, and estimate for prevalence of deficiency state. Br J Haematol 2001; 113: 636-641.
- 13 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.
- 14 Formstone CJ, Wacey AI, Berg L-P. et al. 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.
- 15 Gomez E, Poort SR, Bertina RM. et al. Identification of eight point mutations in protein S deficiency type I - Analysis of 15 pedigrees. Thromb Haemost 1995; 73: 750-755.
- 16 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.
- 17 Borgel D, Duchemin J, Alhenc-Gelas M. et al. and the French network on molecular abnormalities responsible for protein C and protein S deficiencies. Molecular basis for protein S hereditary deficiency: genetic defects observed in 118 patients with type I and type IIa deficiencies. J Lab Clin Med 1996; 128: 218-227.
- 18 Duchemin J, Borg J-Y, Borgel D. et al. Five novel mutations of the protein S active gene (PROS1) in 8 Norman families. Thromb Haemost 1996; 75: 437-444.
- 19 Simmonds RE, Ireland H, Kunz G. et al. Identification of 19 protein S gene mutations in patients with phenotypic protein S deficiency and thrombosis. Blood 1996; 88: 4195-4204.
- 20 Bustorff TC, Freire I, Gago T, et a l. Identification of three novel mutations in hereditary protein S deficiency. Thromb Haemost 1997; 77: 21-25.
- 21 Espinosa-Parrilla Y, Morell M, Souto JC. et al. 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.
- 22 Espinosa-Parrilla Y, Morell M, Borrell M. et al. Optimization of a simple and rapid single-strand conformation analysis for detection of mutations in the PROS1 gene: identification of seven novel mutations and three novel, apparently neutral, variants. Hum Mutat 2000; 15: 463-473.
- 23 Iwaki T, Matsushita T, Kobayashi T. et al. DNA sequence analysis of protein S deficiency - identification of four point mutations in twelve Japanese subjects. Sem Thromb Hemost 2001; 27: 155-160.
- 24 Rezende SM, Lane DA, Zöller B. et al. Genetic and phenotypic variability between families with hereditary protein S deficiency. Thromb Haemost 2002; 87: 258-265.
- 25 Labrouche S, Reboul M-P, Guérin V. et al. Protein C and protein S assessment in hospital laboratories: which strategy and what role for DNA sequencing?. Blood Coagul Fibrinolysis 2003; 14: 531-538.
- 26 Lanke E, Johansson AM, Hillarp A. et al. Co-segregation of the PROS1 locus and protein S deficiency in families having no detectable mutations in PROS1. J Thromb Haemost 2004; 02: 1918-1923.
- 27 Johansson AM, Hillarp A, Säll T. et al. Large deletions of the protein S gene in a large fraction of mutation-negative patients with protein S deficiency. Thromb Haemost 2005; 94: 951-957.
- 28 Simmonds RE, Zöller B, Ireland H. et al. Genetic and phenotypic analysis of a large (122-member) protein S-deficient kindred provides an explanation for the familiar coexistence of type I and III plasma phenotypes. Blood 1997; 89: 4364-4370.
- 29 Simmonds RE, Ireland H, Lane DA. et al. Clarification of the risk for venous thrombosis associated with hereditary protein S deficiency by investigation of a large kindred with a characterized gene defect. Ann Intern Med 1998; 128: 8-14.
- 30 Zöller B, García 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.
- 31 Zöller B, Berntsdotter A, García de Frutos P. et al. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood 1995; 85: 3518-3523.
- 32 Schouten J P, McElgunn CJ, Waaijer R. et al. Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucleic Acids Res 2002; 30: e57.
- 33 Yin T, Takeshita S, Sato Y. et al. A large deletion of the PROS1 gene in a deep vein thrombosis patient with protein S deficiency. Thromb Haemost 2007; 98: 783-789.
- 34 Yoo JH, Kim HJ, Maeng HY. et al. Hereditary protein S deficiency from a novel large deletion mutation of the PROS1 gene detected by multiplex ligation-dependent probe amplification (MLPA). Thromb Res 2009; 123: 793-795.
- 35 Choung HS, Kim HJ, Gwak G Y. et al. Inherited protein S deficiency as a result of a large duplication mutation of the PROS1 gene detected by multiplex ligation-dependent probe amplification. J Thromb Haemost 2008; 06: 1430-1432.
- 36 Hurtado B, Nadal M, Margarit E. et al. First case of protein S deficiency due to a translocation t(3;21)(q11.2;q22). Thromb Haemost 2009; 101: 977-979.
- 37 Pintao MC, Garcia AA, Borgel D. et al. Gross deletions/duplications in PROS1 are relatively common in point mutation-negative hereditary protein S deficiency. Hum Genet 2009; 126: 449-456.
- 38 Ten Kate MK, Platteel M, Mulder R. et al. PRO S1 analys is in 87 pedigrees with hereditary protein S deficiency demonstrates striking genotype-phenotype associations. Hum Mutat 2008; 29: 939-947.
- 39 Castoldi E, Maurissen LF, Tormene D. et al. Similar hypercoagulable state and thrombosis risk in type I and type III protein S-deficient individuals from families with mixed type I/III protein S deficiency. Haematologica 2010; 95: 1563-1571.
- 40 de Wolf CJF, Cupers RMJ, Bertina RM. et al. The constitutive expression of anticoagulant protein S is regulated through multiple binding sites for Sp1 and Sp3 transcription factors in the protein S gene promoter. J Biol Chem 2006; 281: 17635-17643.
- 41 Tatewaki H, Tsuda H, Kanaji T. et al. Characterization of the human protein S gene promoter: a possible role of transcription factors Sp1 and HNF3 in liver. Thromb Haemost 2003; 90: 1029-1039.