ORPHA: 743; DO: 0111900;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q11.1 | Thrombophilia 5 due to protein S deficiency, autosomal dominant | 612336 | Autosomal dominant | 3 | PROS1 | 176880 |
A number sign (#) is used with this entry because of evidence that thrombophilia due to protein S deficiency (THPH5) is caused by heterozygous mutation in the gene encoding protein S (PROS1; 176880) on chromosome 3q11.
Heterozygous protein S deficiency, like protein C deficiency (176860), is characterized by recurrent venous thrombosis. Bertina (1990) classified protein S deficiency into 3 clinical subtypes based on laboratory findings. Type I refers to deficiency of both free and total protein S as well as decreased protein S activity; type II shows normal plasma values, but decreased protein S activity; and type III shows decreased free protein S levels and activity, but normal total protein S levels. Approximately 40% of protein S circulates as a free active form, whereas the remaining 60% circulates as an inactive form bound to C4BPA (120830).
Zoller et al. (1995) observed coexistence of type I and type III PROS1-deficient phenotypes within a single family and determined that the subtypes are allelic. Under normal conditions, the concentration of protein S exceeds that of C4BPA by approximately 30 to 40%. Thus, free protein S is the molar surplus of protein S over C4BPA. Mild protein S deficiency will thus present with selective deficiency of free protein S, whereas more pronounced protein S deficiency will also decrease the complexed protein S and consequently the total protein S level. These findings explained why assays for free protein S have a higher predictive value for protein S deficiency.
See also autosomal recessive thrombophilia due to protein S deficiency (THPH6; 614514), which is a more severe disorder.
Comp and Esmon (1984) found partial protein S deficiency in 6 unrelated persons with severe recurrent venous thrombosis. Serum protein S levels ranged from 15 to 37% of normal values. Family histories were consistent with autosomal dominant inheritance. Some asymptomatic family members had equally low levels of protein S, suggesting that additional factors may be necessary to precipitate thrombosis.
Schwarz et al. (1984) found low plasma protein S in 4 persons spanning 2 generations of a family. All had severe recurrent thromboembolic disease.
Engesser et al. (1987) analyzed the clinical manifestations of protein S deficiency in 136 members of 12 families with the disorder; 71 persons were heterozygous for the deficiency. Venous thrombotic events occurred in 39 (55%) of patients and were recurrent in 77% of these. Symptomatic patients had various combinations of deep venous thrombosis (74%), superficial thrombophlebitis (72%), and pulmonary embolism (38%), either in succession or simultaneously. In 5 instances, thrombosis occurred at unusual sites, such as the axillary, mesenteric, and cerebral veins. The age at first thrombotic event ranged from 15 to 68 years. At age 35, the probability of still being free of thrombosis was only 32%. There was no preceding precipitating condition in 56% of thrombotic events.
In a woman who developed deep vein thrombosis while taking oral contraceptives, Mannucci et al. (1989) found a dysfunctional protein S, present in plasma in normal amounts and with normal proportions of the free and complexed forms. Five other family members in the same and the preceding generation had the same laboratory abnormality but were asymptomatic.
Chafa et al. (1989) reported 2 sibs, a 26-year-old woman and her 28-year-old brother, who had recurrent venous thrombosis since the age of 20. Laboratory studies showed severe protein S deficiency with 2.5 to 3% free protein levels and less than 20% total protein levels. Crossed immunoelectrophoresis using anti-protein S antibodies revealed no free protein S. Three children of the sister had less severe protein S deficiency with total protein S levels ranging from 41 to 50% and free protein S levels ranging from 16 to 18%. Chafa et al. (1989) concluded that the proposita and her brother had type II protein S deficiency, whereas the proposita's children had type I deficiency.
Sacco et al. (1989) presented evidence suggesting that protein S deficiency may be a cause not only of venous thrombosis, but also of arterial occlusive disease, specifically cerebrovascular occlusion. In a group of 37 consecutive patients with arterial occlusive disease presenting before the age of 45, Allaart et al. (1990) found 3 who were heterozygous for protein S deficiency.
Golub et al. (1990) described central retinal artery occlusion in a 30-year-old man with protein S deficiency. He had had multiple episodes of venous and arterial thrombosis, including deep venous thrombosis in the legs with pulmonary embolism and arterial thrombosis requiring amputation of the legs and left aortoiliac bypass.
Girolami et al. (1990) reported a large Italian kindred with recurrent thrombophilia associated with heterozygous protein S deficiency.
Clark et al. (1991) described a 26-year-old college student who developed acute mesenteric vein thrombosis. His total protein S concentration was normal, but by assay and on crossed immunoelectrophoresis studies, he had decreased concentration of free protein S. His father and a sister similarly showed protein S deficiency.
Koller et al. (1994) described 2 sisters who were heterozygotes for both protein C and protein S deficiency and who suffered occlusive infarcts in the distributions of the anterior and middle cerebral arteries at ages 40 and 27, respectively. Their mother had borderline levels of protein C and protein S and suffered from cerebrovascular accident at age 68. One brother showed deficiency of protein C only, whereas 3 other sibs showed no deficiency of either protein; 1 child of the proband had a deficiency of protein S.
Leung et al. (2010) reported a 3-generation Chinese family in which 6 members had autosomal dominant protein S deficiency confirmed by genetic analysis (R355C; 176880.0009). The proband was a 43-year-old man who presented with acute left hemiparesis due to acute cerebral ischemic infarction. Two other family members with the deficiency also presented in their forties with cryptogenic ischemic strokes. The heterozygous mutation was found in 3 additional family members who were asymptomatic at age 42, 20, and 13 years. Laboratory studies of all mutation carriers showed protein S deficiency type III, with decreased free protein S levels and activity, but normal total protein levels. Brain MRI of all 3 affected individuals and 2 of the asymptomatic individuals showed white matter infarctions in the internal and external border zones, with some extension into the paraventricular white matter regions in those with higher infarct volume. The cerebral cortex was spared. The findings indicated that protein S deficiency induces a hypercoagulable state that predisposes to arteriolar thrombosis in certain regions of the cerebral vasculature.
Acquired Protein S Deficiency
A phenocopy of hereditary protein S deficiency was reported by D'Angelo et al. (1993) in an 11-year-old boy who developed severe thromboembolic disease associated with a transient isolated deficiency of protein S due to the presence of a circulating autoantibody; complication occurred during recovery from chickenpox. Malnick and Sthoeger (1993) suggested that anticardiolipin antibodies, which can be detected transiently after viral infections, may have been the pathogenic anti-protein S antibodies in the case of D'Angelo et al. (1993).
Pan et al. (1990) reported 2 children with typical inherited protein S deficiency which resulted in serious episodes of thrombosis at multiple sites. Both also had severe osteopenia and a decrease in bone mineral density. In one of them, osteopenia was associated with vertebral body compression fractures. Pan et al. (1990) posited that a protein S deficiency might be associated with abnormalities of bone mineral density. Maillard et al. (1992) found that protein S is synthesized by human osteoblasts in an active form and incorporated in the mineralized matrix of bone. Previously, protein S was known to be synthesized mostly by hepatocytes.
Makris et al. (2000) stated that protein S deficiency has such marked phenotypic variability that it is the most difficult to diagnose of all the inherited thrombophilic conditions. Among a cohort 109 first-degree relatives of 28 patients with genetically confirmed protein S deficiency, a low free protein S level was the most reliable predictor of a PROS1 gene defect (sensitivity 97.7%, specificity 100%). First-degree relatives with a PROS1 gene defect had a 5.0-fold higher risk of thrombosis compared to relatives with a normal PROS1 gene. Although pregnancy/puerperium and immobility/trauma were important precipitating factors for thrombosis, almost half of the events were spontaneous. Relatives with splice site or major structural defects of the PROS1 gene were more likely to have had a thrombotic event and had significantly lower total and free protein S levels than those relatives having missense mutations. Makris et al. (2000) concluded that free protein S estimation offers the most reliable way of diagnosing the deficiency.
Formstone et al. (1995) identified 7 different heterozygous mutations in the PROS1 gene (see, e.g., 176880.0002) in patients with protein S deficiency.
In affected members of 22 Spanish families with protein S deficiency, Espinosa-Parrilla et al. (1999) identified 10 different mutations in the PROS1 gene (see, e.g., 176880.0007; 176880.0008). One of these mutations, Q238X (176880.0007), cosegregated with both type I and type III protein S-deficient phenotypes coexisting in a type I/type III pedigree. By contrast, Espinosa-Parrilla et al. (1999) found no cosegregating PROS1 mutations in any of the 6 families with only type III phenotypes. From these results, Espinosa-Parrilla et al. (1999) concluded that while mutations in PROS1 are the main cause of type I protein S deficiency, the molecular basis of the type III phenotype may be more complex.
Using multiplex ligation-dependent probe amplification (MLPA) analysis, Pintao et al. (2009) identified copy number variation (CNV) involving the PROS1 gene in 6 (33%) of 18 probands with protein S deficiency who did not have point mutations by direct sequencing. The results were confirmed by PCR analysis. Three probands were found to have complete deletion of the PROS1 gene; all had type I deficiency with quantitative deficiency of total and free PROS1 antigen. Two probands had partial deletion, and 1 proband had partial duplication. Two probands with complete deletion and the proband with partial duplication had positive family history and the CNV cosegregated with protein S deficiency in family members.
Allaart, C. F., Aronson, D. C., Ruys, T., Rosendaal, F. R., van Bockel, J. H., Bertina, R. M., Briet, E. Hereditary protein S deficiency in young adults with arterial occlusive disease. Thromb. Haemost. 64: 206-210, 1990. [PubMed: 2148653]
Bertina, R. M. Nomenclature proposal for protein S deficiency. XXXVI Annual meeting of the Scientific and Standardization Committee of the ISTH. Barcelona, Spain 1990.
Chafa, O., Fischer, A. M., Meriane, F., Chellali, F., Rahal, S., Sternberg, C., Benabadji, M. A new case of 'type II' inherited protein S deficiency. Brit. J. Haemat. 73: 501-505, 1989. [PubMed: 2532929] [Full Text: https://doi.org/10.1111/j.1365-2141.1989.tb00288.x]
Clark, D. A., Williams, W. L., Marlar, R. A. Mesenteric vein thrombosis associated with a familial deficiency of free protein S. Arch. Path. Lab. Med. 115: 617-619, 1991. [PubMed: 1828142]
Comp, P. C., Esmon, C. T. Recurrent venous thromboembolism in patients with a partial deficiency of protein S. New Eng. J. Med. 311: 1525-1528, 1984. [PubMed: 6239102] [Full Text: https://doi.org/10.1056/NEJM198412133112401]
D'Angelo, A., Della Valle, P., Crippa, L., Pattarini, E., Grimaldi, L. M. E., D'Angelo, S. V. Autoimmune protein S deficiency in a boy with severe thromboembolic disease. New Eng. J. Med. 328: 1753-1757, 1993. [PubMed: 8497285] [Full Text: https://doi.org/10.1056/NEJM199306173282405]
Engesser, L., Broekmans, A. W., Briet, E., Brommer, E. J. P., Bertina, R. M. Hereditary protein S deficiency: clinical manifestations. Ann. Intern. Med. 106: 677-682, 1987. [PubMed: 2952034] [Full Text: https://doi.org/10.7326/0003-4819-106-5-677]
Espinosa-Parrilla, Y., Morell, M., Souto, J. C., Tirado, I., Fontcuberta, J., Estivill, X., Sala, N. 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. 14: 30-39, 1999. [PubMed: 10447256] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1999)14:1<30::AID-HUMU4>3.0.CO;2-X]
Formstone, C. J., Wacey, A. I., Berg, L.-P., Rahman, S., Bevan, D., Rowley, M., Voke, J., Bernardi, F., Legnani, C., Simioni, P., Girolami, A., Tuddenham, E. G. D., Kakkar, V. V., Cooper, D. N. Detection and characterization of seven novel protein S (PROS) gene lesions: evaluation of reverse transcript-polymerase chain reaction as a mutation screening strategy. Blood 86: 2632-2641, 1995. [PubMed: 7545463]
Girolami, A., Simioni, P., Lazzaro, A. R., Pontara, E., Ruzza, G. Heterozygous protein-S deficiency: a study of a large kindred. Acta Haemat. 84: 162-168, 1990. [PubMed: 2147089] [Full Text: https://doi.org/10.1159/000205055]
Golub, B. M., Sibony, P. A., Coller, B. S. Protein S deficiency associated with central retinal artery occlusion. Arch. Ophthal. 108: 918 only, 1990. [PubMed: 2142417] [Full Text: https://doi.org/10.1001/archopht.1990.01070090020012]
Koller, H., Stoll, G., Sitzer, M., Burk, M., Schottler, B., Freund, H-J. Deficiency of both protein C and protein S in a family with ischemic strokes in young adults. Neurology 44: 1238-1240, 1994. [PubMed: 8035922] [Full Text: https://doi.org/10.1212/wnl.44.7.1238]
Leung, T. W., Yip, S.-F., Lam, C.-W., Chan, T. L., Lam, W. W. M., Siu, D. Y. W., Fan, Y. H., Chan, N. P. H., Liu, H. S. Y., Chan, L.-C., Wong, K.-S. Genetic predisposition of white matter infarction with protein S deficiency and R355C mutation. Neurology 75: 2185-2189, 2010. [PubMed: 21172841] [Full Text: https://doi.org/10.1212/WNL.0b013e3182020379]
Maillard, C., Berruyer, M., Serre, C. M., Dechavanne, M., Delmas, P. D. Protein-S, a vitamin K-dependent protein, is a bone matrix component synthesized and secreted by osteoblasts. Endocrinology 130: 1599-1604, 1992. [PubMed: 1531628] [Full Text: https://doi.org/10.1210/endo.130.3.1531628]
Makris, M., Leach, M., Beauchamp, N. J., Daly, M. E., Cooper, P. C., Hampton, K. K., Bayliss, P., Peake, I. R., Miller, G. J., Preston, F. E. Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis in families with inherited deficiencies of protein S. Blood 95: 1935-1941, 2000. [PubMed: 10706858]
Malnick, S. D. H., Sthoeger, Z. M. Autoimmune protein S deficiency. New Eng. J. Med. 329: 1898 only, 1993. [PubMed: 8247052] [Full Text: https://doi.org/10.1056/NEJM199312163292519]
Mannucci, P. M., Valsecchi, C., Krachmalnicoff, A., Faioni, E. M., Tripodi, A. Familial dysfunction of protein S. Thromb. Haemost. 62: 763-766, 1989. [PubMed: 2530648]
Pan, E. Y., Gomperts, E. D., Millen, R., Gilsanz, V. Bone mineral density and its association with inherited protein S deficiency. Thromb. Res. 58: 221-231, 1990. [PubMed: 2141197] [Full Text: https://doi.org/10.1016/0049-3848(90)90092-q]
Phillips, W. G., Marsden, J. R., Hill, F. G. Purpura fulminans due to protein S deficiency following chickenpox. Brit. J. Derm. 127: 30-32, 1992. [PubMed: 1386247] [Full Text: https://doi.org/10.1111/j.1365-2133.1992.tb14821.x]
Pintao, M. C., Garcia, A. A., Borgel, D., Alhenc-Gelas, M., Spek, C. A., de Visser, M. C. H., Gandrille, S., Reitsma, P. H. Gross deletions/duplications in PROS1 are relatively common in point mutation-negative hereditary protein S deficiency. Hum. Genet. 126: 449-456, 2009. [PubMed: 19466456] [Full Text: https://doi.org/10.1007/s00439-009-0687-9]
Sacco, R. L., Owen, J., Mohr, J. P., Tatemichi, T. K., Grossman, B. A. Free protein S deficiency: a possible association with cerebrovascular occlusion. Stroke 20: 1657-1661, 1989. [PubMed: 2531944] [Full Text: https://doi.org/10.1161/01.str.20.12.1657]
Sas, G., Blasko, G., Petro, I., Griffin, J. H. A protein S deficient family with portal vein thrombosis. (Letter) Thromb. Haemost. 54: 724 only, 1985. [PubMed: 2935967]
Schwarz, H. P., Fischer, M., Hopmeier, P., Batard, M. A., Griffin, J. H. Plasma protein S deficiency in familial thrombotic disease. Blood 64: 1297-1300, 1984. [PubMed: 6238642]
Zoller, B., Garcia de Frutos, P., Dahlback, 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 85: 3524-3531, 1995. [PubMed: 7780139]