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DOI: 10.1055/s-0037-1614891
Poor Relationship between Phenotypes of Protein S Deficiency and Mutations in the Protein S Alpha Gene
This work was supported by institutional grants by I.R.C.C.S. Maggiore Hospital. José Hermida was supported by a fellowship from the Spanish Ministry of Health ”Beca de Ampliación de Estudios” (BAE 98/5031).Publication History
Received
24 May 1999
Accepted after revision
24 August 1999
Publication Date:
10 December 2017 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/199906/lookinside/thumbnails/10-1055s-0037-1614891-1.jpg)
Summary
By single strand conformational polymorphism, nucleotide sequencing and enzyme restriction, we analyzed the protein S α gene in 17 protein S-deficient probands and in their available family members. The relationship between genotype and phenotype was also evaluated. Twelve different sequence variations were identified in 17 probands. Ten were putative causal mutations distributed in 16 probands: 4 were nonsense, 5 missense and one a splice site mutation. In most families in which a mutation was identified, more than one phenotype of PS deficiency was present. The same splice site mutation (intron j G-A, exon 10+5) was associated with type I deficiency in one family and with type I/III in another unrelated family. A phenotypic discrepancy was also observed for the Arg474Pro, Gly597Asp and Arg410stop mutations. Glu26Ala, previously reported in kindreds with type I deficiencies, was found in association with I, II and III phenotypes in four unrelated kindreds. Phenotypic analysis of protein S deficiency is poorly related to the underlying genetic defect.
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References
- 1 De Stefano V, Finazzi G, Mannucci PM. Inherited thrombophilia: Pathogenesis, clinical syndromes, and management. Blood 1996; 87: 3531-44.
- 2 Zöller B, García de Frutos P, Dahlbäck B. Evaluation of the relation between protein S and C4b- binding protein isoforms in hereditary protein S deficiency demostrating type I and type III deficiencies to be phenotypic variants of the same genetic disease. Blood 1995; 85: 3524-31.
- 3 Simmonds RE, Zöller B, Ireland H, Thompson E, García de Frutos P, Dahlbäck B, Lane DA. Genetic and phenotypic analysis of a large (122-member) Protein S-deficient kindred provides an explanation for the familial coexistence of type I and type III plasma phenotypes. Blood 1997; 89: 4364-70.
- 4 Faioni EM, Franchi F, Asti D, Sacchi E, Bernardi F, Mannucci PM. Resistance to activated protein C in nine thrombophilic families: Interference in a protein S functional assay. Thromb Haemost 1993; 70: 1067-71.
- 5 Watkins P, Eddy R, Fukushima Y, Byers M, Cohen E, Dackowski W, Wydro R, Shows T. The gene for protein S maps near the centromer of human chromosome 3. Bood 1988; 71: 238-41.
- 6 Schmidel DK, Tatro AV, Phelps LG, Tomczak JA, Long GL. Organization of the human protein S genes. Biochemistry 1990; 29: 7845-52.
- 7 Gandrille S, Borgel D, Ireland H, Lane DA, Simmonds RE, 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 data base of mutations. Thromb Haemost 1997; 77: 1201-14.
- 8 Andersen BD, Lind B, Philips M, Hansen AB, Ingerslev J, Thorsen S. Two mutations in exon XII of the protein Sα gene in four thrombophilic families resulting in premature stop codons and depressed levels of mutated mRNA. Thromb Haemost 1996; 76: 143-50.
- 9 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.
- 10 Mustafa S, Pabinger I, Vàradi K, Halbmayer W-M, Lechner K, Schwarz Fischer M, Mannhalter C. A hitherto unknown splice site defect in the protein S gene (PROS1): the mutation results in allelic exclusion and causes type I and III protein S deficiency. Br J Haematol 1997; 99: 298-300.
- 11 Beauchamp NJ, Daly ME, Makris M, Preston FE, Peake IR. 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. Thromb Haemost 1998; 79: 1086-91.
- 12 Espinosa-Parrilla Y, Morell M, Souto JC, Borrell M, Heine-Suñer D, Tirado I, Volpini V, Estivill X, Sala N. Absence of linkage between Type III protein S deficiency and the PROS1 and C4BP genes in families carrying the protein S Heerlen Allele. Blood 1997; 89: 2799-806.
- 13 Bertina RM, Ploos van Hamstel HK, van Wiingaarden A, Coenen J, Leeemhuis MP. Heerlen polymorphism of protein S, an immunologic polymorphism due to dimorphism of residue 460. Blood 1990; 76: 538-48.
- 14 Duchemin J, Gandrille S, Borgel D, Feugard P, Alhenc-Gelas M, Matheron C, Dreyfus M, Dupuy E, Juhan-Vague I, Aiach M. The Ser 460 to Pro substitution of the protein S alpha (PROS1) gene is a frequent mutation associated with free protein S (type IIa) deficiency. Blood 1995; 86: 3436-43.
- 15 Leroy-Matheron C, Gouault-Heilmann M, Aiach M, Gandrille S. A mutation of the active protein S gene leading to a an EGF1-lacking protein in a family with qualitative (type II) deficiency. Blood 1998; 91: 4608-15.
- 16 de Ronde H, Bertina RM. Laboratory diagnosis of APC-resistance: a critical evaluation of the test and the development of diagnostic criteria. Thromb Haemost 1994; 72: 880-6.
- 17 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 a increase in venous thrombosis. Blood 1996; 8: 3698-703.
- 18 Faioni EM, Valsecchi C, Palla A, Taioli E, Razzari C, Mannucci PM. Free protein S deficiency is a risk factor for venous thrombosis. Thromb Haemost 1997; 78: 1343-6.
- 19 Preda L, Tripodi A, Valsecchi C, Lombardi A, Finotto E, Mannucci PM. A prothrombin time-based functional assay of protein S. Thromb Res 1990; 60: 19-32.
- 20 Faioni EM. Protein S activity. In: Laboratory techniques in thrombosis. Jespersen J, Bertina RM, Haverkate F. (eds). Dordrecht, The Netherlands: Kluwer Academic Publishers BV; 1999
- 21 Heker KH, Roux KH. High and low annealing temperatures increase both specificity and yield in TD and SD PCR. BioTechniques 1996; 20: 478-85.
- 22 Nishioka J, Ido M, Hayashi T, Suzuki K. The Gla26 residue of protein C is required for the binding of protein C to thrombomodulin and endothelial cell protein C receptor, but not to protein S and factor Va. Thromb Haemost 1996; 75: 275-82.
- 23 Giannelli F, Green PM, High A, Sommer S, Ludwing K, Olek K, Reitsma PH, Goossens M, Yoshioka A. Brownlee Haemophilia B: database of point mutations and short additions and deletions-third edition. Nucleic Acids Res 1992; 20: 2027-63.
- 24 Sacchi E, Pinotti M, Marchetti G, Merati G, Tagliabue L, Mannucci PM. Bernardi Protein S mRNA in patients with protein S deficiency. Thromb Haemost 1995; 73: 746-49
- 25 Reitsma PH, Bernardi 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. On behalf of the Subcommittee on Plasma Coagulation Inhibitors of the Scientific and Standardization Committee of the ISTH. Thromb Haemost 1995; 73: 876-89.
- 26 Toulon P, Gandrille S, Vitoux JF, Fiessinger JN, Sultan Y, Aiach M. High total and free protein S in patients with acute deep vein thrombosis. Thromb Res 1990; 59: 213-7.
- 27 Lawrie AS, Lloyd ME, Mohamed F, Irons S, Hughes GR, Savidge GF. Assay of protein S in systemic lupus erythematosus. Blood Coag Fibrinol 1995; 6: 322-4.
- 28 Boyer-Neumann C, Bertina RM, Tripodi A, D’Angelo A, Wolf M, Vigano’ D’Angelo S, Mannucci PM, Meyer D, Larrieu MJ. Comparison of functional assays for protein S: European collaborative study of patients with congenital and acquired deficiency. Thromb Haemost 1993; 70: 946-50.
- 29 Gandrille S, Borgel D, Eschwege-Gufflet V, Aillaud MF, Dreyfus M, Duchemin J, Matheron C, Gaussem P, Abgrall JF, Jude B, Sie P, Toulon P, Aiach M. Identification of different candidate causal point mutations and three polymorphisms in 19 patients with protein S deficiency using a scanning method for the analysis of the protein S active gene. Blood 1995; 85: 130-8.
- 30 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.