RBCC Red Blood Cell Collection

PROS1 (PROS) [Confidence: low (only semi-automatic identification from reviews)]
Vitamin K-dependent protein S; Flags: Precursor
Note: presumably soluble (membrane word is not in UniProt keywords or features)

UniProt P07225
ID PROS_HUMAN Reviewed; 676 AA.
AC P07225; A8KAC9; D3DN28; Q15518; Q7Z715; Q9UCZ8;
DT 01-APR-1988, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-APR-1988, sequence version 1.
DT 22-JAN-2014, entry version 178.
DE RecName: Full=Vitamin K-dependent protein S;
DE Flags: Precursor;
GN Name=PROS1; Synonyms=PROS;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=2820795; DOI=10.1016/0014-5793(87)80217-X;
RA Ploos van Amstel H.K., van der Zanden A.L., Reitsma P.H.,
RA Bertina R.M.;
RT "Human protein S cDNA encodes Phe-16 and Tyr 222 in consensus
RT sequences for the post-translational processing.";
RL FEBS Lett. 222:186-190(1987).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3467362; DOI=10.1073/pnas.84.2.349;
RA Hoskins J., Norman D.K., Beckmann R.J., Long G.L.;
RT "Cloning and characterization of human liver cDNA encoding a protein S
RT precursor.";
RL Proc. Natl. Acad. Sci. U.S.A. 84:349-353(1987).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=2148110; DOI=10.1021/bi00486a010;
RA Schmidel D.K., Tatro A.V., Phelps L.G., Tomczak J.A., Long G.L.;
RT "Organization of the human protein S genes.";
RL Biochemistry 29:7845-7852(1990).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Liver;
RX PubMed=2148111; DOI=10.1021/bi00486a011;
RA Ploos van Amstel H.K., Reitsma P.H., der Logt C.P., Bertina R.M.;
RT "Intron-exon organization of the active human protein S gene PS alpha
RT and its pseudogene PS beta: duplication and silencing during primate
RT evolution.";
RL Biochemistry 29:7853-7861(1990).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Trachea;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG SeattleSNPs variation discovery resource;
RL Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Uterus;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 27-676.
RX PubMed=2944113; DOI=10.1073/pnas.83.18.6716;
RA Lundwall A., Dackowski W., Cohen E., Shaffer M., Mahr A., Dahlback B.,
RA Stenflo J., Wydro R.;
RT "Isolation and sequence of the cDNA for human protein S, a regulator
RT of blood coagulation.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:6716-6720(1986).
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 500-519, AND VARIANTS THPH5
RP VAL-381 AND GLY-508.
RX PubMed=7482398;
RA Gomez E., Poort S.R., Bertina R.M., Reitsma P.H.;
RT "Identification of eight point mutations in protein S deficiency type
RT I -- analysis of 15 pedigrees.";
RL Thromb. Haemost. 73:750-755(1995).
RN [11]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-530, AND MASS
RP SPECTROMETRY.
RC TISSUE=Plasma;
RX PubMed=16335952; DOI=10.1021/pr0502065;
RA Liu T., Qian W.-J., Gritsenko M.A., Camp D.G. II, Monroe M.E.,
RA Moore R.J., Smith R.D.;
RT "Human plasma N-glycoproteome analysis by immunoaffinity subtraction,
RT hydrazide chemistry, and mass spectrometry.";
RL J. Proteome Res. 4:2070-2080(2005).
RN [12]
RP STRUCTURE BY NMR OF 200-286, AND DISULFIDE BONDS.
RX PubMed=15952784; DOI=10.1021/bi050101f;
RA Drakenberg T., Ghasriani H., Thulin E., Thamlitz A.M., Muranyi A.,
RA Annila A., Stenflo J.;
RT "Solution structure of the Ca2+-binding EGF3-4 pair from vitamin K-
RT dependent protein S: identification of an unusual fold in EGF3.";
RL Biochemistry 44:8782-8789(2005).
RN [13]
RP VARIANT PRO-501.
RX PubMed=2143091;
RA Bertina R.M., Ploos van Amstel H.K., van Wijngaarden A., Coenen J.,
RA Leemhuis M.P., Deutz-Terlouw P.P., van der Linden I.K., Reitsma P.H.;
RT "Heerlen polymorphism of protein S, an immunologic polymorphism due to
RT dimorphism of residue 460.";
RL Blood 76:538-548(1990).
RN [14]
RP VARIANT THPH5 SER-258.
RA Cooper D.N.;
RL Unpublished observations (SEP-1993).
RN [15]
RP VARIANT THPH5 TOKUSHIMA GLU-196.
RX PubMed=8298131;
RA Hayashi T., Nishioka J., Shigekiyo T., Saito S., Suzuki K.;
RT "Protein S Tokushima: abnormal molecule with a substitution of Glu for
RT Lys-155 in the second epidermal growth factor-like domain of protein
RT S.";
RL Blood 83:683-690(1994).
RN [16]
RP VARIANTS THPH5 LEU-40; HIS-41; ALA-67; CYS-72; MET-78; HIS-90;
RP ASN-144; GLY-245; LYS-249; TRP-265; ARG-265 AND ASN-376, AND VARIANTS
RP LEU-76 AND VAL-385.
RX PubMed=7803790;
RA Gandrille S., Borgel D., Eschwege-Gufflet V., Aillaud M., Dreyfus M.,
RA Matheron C., Gaussem P., Abgrall J.F., Jude B., Sie P., Toulon P.,
RA Aiach M.;
RT "Identification of 15 different candidate causal point mutations and
RT three polymorphisms in 19 patients with protein S deficiency using a
RT scanning method for the analysis of the protein S active gene.";
RL Blood 85:130-138(1995).
RN [17]
RP VARIANTS THPH5 SER-258 AND THR-611.
RX PubMed=7545463;
RA Formstone C.J., Wacey A.I., Berg L.-P., Rahman S., Bevan D.,
RA Rowley M., Voke J., Bernardi F., Legnani C., Simioni P., Girolami A.,
RA Tuddenham E.G.D., Kakkar V.V., Cooper D.N.;
RT "Detection and characterization of seven novel protein S (PROS) gene
RT lesions: evaluation of reverse transcript-polymerase chain reaction as
RT a mutation screening strategy.";
RL Blood 86:2632-2641(1995).
RN [18]
RP VARIANTS THPH5 PRO-351; SER-552; GLN-584 AND PRO-616.
RX PubMed=7579449;
RA Mustafa S., Pabinger I., Mannhalter C.;
RT "Protein S deficiency type I: identification of point mutations in 9
RT of 10 families.";
RL Blood 86:3444-3451(1995).
RN [19]
RP VARIANT THPH5 SER-644.
RX PubMed=8977443;
RA Li M., Long G.L.;
RT "Identification of two novel point mutations in the human protein S
RT gene associated with familial protein S deficiency and thrombosis.";
RL Arterioscler. Thromb. Vasc. Biol. 16:1407-1415(1996).
RN [20]
RP VARIANT THPH5 CYS-515, CHARACTERIZATION OF VARIANT PROS1 DEFICIENCY
RP CYS-515, AND MUTAGENESIS OF ARG-515.
RX PubMed=8639833;
RA Yamazaki T., Katsumi A., Kagami K., Okamoto Y., Sugiura I.,
RA Hamaguchi M., Kojima T., Takamatsu J., Saito H.;
RT "Molecular basis of a hereditary type I protein S deficiency caused by
RT a substitution of Cys for Arg474.";
RL Blood 87:4643-4650(1996).
RN [21]
RP VARIANTS THPH5 TYR-186; THR-611 AND LEU-665.
RX PubMed=8781426;
RA Beauchamp N.J., Daly M.E., Cooper P.C., Makris M., Preston F.E.,
RA Peake I.R.;
RT "Molecular basis of protein S deficiency in three families also
RT showing independent inheritance of factor V Leiden.";
RL Blood 88:1700-1707(1996).
RN [22]
RP VARIANTS THPH5 GLU-50; ALA-67; GLU-95; TYR-186; SER-241; PRO-324;
RP ASP-381; SER-449 AND ARG-666, AND VARIANT PRO-501.
RX PubMed=8943854;
RG Protein S study group;
RA Simmonds R.E., Ireland H., Kunz G., Lane D.A.;
RT "Identification of 19 protein S gene mutations in patients with
RT phenotypic protein S deficiency and thrombosis.";
RL Blood 88:4195-4204(1996).
RN [23]
RP VARIANTS THPH5 SER-111; GLY-157; GLY-161; GLU-364; PRO-446; ARG-475;
RP ALA-501; MET-508; CYS-515; PRO-525; ALA-532; TYR-568; ARG-575 AND
RP ARG-666, AND VARIANT PRO-501.
RX PubMed=8765219; DOI=10.1016/S0022-2143(96)90015-3;
RG The French network on molecular abnormalities responsible for protein C and protein S deficiencies;
RA Borgel D., Duchemin J., Alhenc-Gelas M., Matheron C., Aiach M.,
RA Gandrille S.;
RT "Molecular basis for protein S hereditary deficiency: genetic defects
RT observed in 118 patients with type I and type IIa deficiencies.";
RL J. Lab. Clin. Med. 128:218-227(1996).
RN [24]
RP VARIANTS THPH5 PRO-300 AND ARG-666.
RX PubMed=8701404;
RA Duchemin J., Borg J.-Y., Borgel D., Vasse M., Leveque H., Aiach M.,
RA Gandrille S.;
RT "Five novel mutations of the protein S active gene (PROS 1) in 8
RT Norman families.";
RL Thromb. Haemost. 75:437-444(1996).
RN [25]
RP VARIANT THPH5 PHE-639.
RX PubMed=9031443;
RA Bustorff T.C., Freire I., Gago T., Crespo F., David D.;
RT "Identification of three novel mutations in hereditary protein S
RT deficiency.";
RL Thromb. Haemost. 77:21-25(1997).
RN [26]
RP VARIANTS THPH5 ASP-68; ARG-95 AND SER-336.
RX PubMed=9241758;
RG Plasma coagulation inhibitors subcommittee of the scientific and standardization committee of the international society on thrombosis and haemostasis;
RA Gandrille S., Borgel D., Ireland H., Lane D.A., Simmonds R.,
RA Reitsma P.H., Mannhalter C., Pabinger I., Saito H., Suzuki K.,
RA Formstone C., Cooper D.N., Espinosa Y., Sala N., Bernardi F.,
RA Aiach M.;
RT "Protein S deficiency: a database of mutations.";
RL Thromb. Haemost. 77:1201-1214(1997).
RN [27]
RP VARIANTS THPH5 CYS-482; CYS-485 AND GLY-561, AND VARIANTS PRO-501 AND
RP MET-559.
RX PubMed=10447256;
RX DOI=10.1002/(SICI)1098-1004(1999)14:1<30::AID-HUMU4>3.3.CO;2-O;
RA Espinosa-Parrilla Y., Morell M., Souto J.C., Tirado I.,
RA Fontcuberta J., Estivill X., Sala N.;
RT "Protein S gene analysis reveals the presence of a cosegregating
RT mutation in most pedigrees with type I but not type III PS
RT deficiency.";
RL Hum. Mutat. 14:30-39(1999).
RN [28]
RP VARIANTS THPH5 ALA-67; GLY-129; PHE-175; PRO-515; LEU-562 AND ASP-638,
RP AND VARIANTS LEU-76 AND ASP-638.
RX PubMed=10613647;
RA Hermida J., Faioni E.M., Mannucci P.M.;
RT "Poor relationship between phenotypes of protein S deficiency and
RT mutations in the protein S alpha gene.";
RL Thromb. Haemost. 82:1634-1638(1999).
RN [29]
RP VARIANTS THPH5 TYR-166; GLY-247; THR-611; ARG-622 AND ARG-666.
RX PubMed=10706858;
RA Makris M., Leach M., Beauchamp N.J., Daly M.E., Cooper P.C.,
RA Hampton K.K., Bayliss P., Peake I.R., Miller G.J., Preston F.E.;
RT "Genetic analysis, phenotypic diagnosis, and risk of venous thrombosis
RT in families with inherited deficiencies of protein S.";
RL Blood 95:1935-1941(2000).
RN [30]
RP VARIANTS THPH5 HIS-15; LYS-233; THR-640 AND LEU-667, AND VARIANTS
RP SER-98 AND MET-559.
RX PubMed=10790208;
RX DOI=10.1002/(SICI)1098-1004(200005)15:5<463::AID-HUMU8>3.3.CO;2-5;
RA Espinosa-Parrilla Y., Morell M., Borrell M., Souto J.C.,
RA Fontcuberta J., Estivill X., Sala N.;
RT "Optimization of a simple and rapid single-strand conformation
RT analysis for detection of mutations in the PROS1 gene: identification
RT of seven novel mutations and three novel, apparently neutral,
RT variants.";
RL Hum. Mutat. 15:463-473(2000).
RN [31]
RP VARIANTS THPH5 ASN-243 AND PRO-339.
RX PubMed=11372770; DOI=10.1055/s-2001-14075;
RA Iwaki T., Mastushita T., Kobayashi T., Yamamoto Y., Nomura Y.,
RA Kagami K., Nakayama T., Sugiura I., Kojima T., Takamatsu J.,
RA Kanayama N., Saito H.;
RT "DNA sequence analysis of protein S deficiency -- identification of
RT four point mutations in twelve Japanese subjects.";
RL Semin. Thromb. Hemost. 27:155-160(2001).
RN [32]
RP VARIANTS THPH5 CYS-149; ARG-383; LYS-390 AND SER-526.
RX PubMed=11776305;
RA Andersen B.D., Bisgaard M.L., Lind B., Philips M., Villoutreix B.O.,
RA Thorsen S.;
RT "Characterization and structural impact of five novel PROS1 mutations
RT in eleven protein S-deficient families.";
RL Thromb. Haemost. 86:1392-1399(2001).
RN [33]
RP VARIANTS THPH5 ASP-52 AND MET-78, AND CHARACTERIZATION OF VARIANTS
RP THPH5 ASP-52 AND MET-78.
RX PubMed=12351389; DOI=10.1182/blood-2002-03-0909;
RA Rezende S.M., Lane D.A., Mille-Baker B., Samama M.M., Conard J.,
RA Simmonds R.E.;
RT "Protein S Gla-domain mutations causing impaired Ca(2+)-induced
RT phospholipid binding and severe functional protein S deficiency.";
RL Blood 100:2812-2819(2002).
RN [34]
RP VARIANTS THPH5 GLU-18; CYS-90; LYS-233; SER-258; VAL-336 AND PRO-664,
RP AND CHARACTERIZATION OF VARIANTS THPH5 GLU-18; CYS-90; LYS-233;
RP SER-258 VAL-336 AND PRO-664.
RX PubMed=11858485;
RA Rezende S.M., Lane D.A., Zoeller B., Mille-Baker B., Laffan M.,
RA Dalhbaeck B., Simmonds R.E.;
RT "Genetic and phenotypic variability between families with hereditary
RT protein S deficiency.";
RL Thromb. Haemost. 87:258-265(2002).
RN [35]
RP VARIANTS THPH5 ARG-95; GLU-196; ILE-630 AND CYS-636, AND
RP CHARACTERIZATION OF VARIANTS THPH5 ARG-95; GLU-196; ILE-630 AND
RP CYS-636.
RX PubMed=11927129; DOI=10.1016/S0049-3848(02)00015-4;
RA Tsuda H., Urata M., Tsuda T., Wakiyama M., Iida H., Nakahara M.,
RA Kinoshita S., Hamasaki N.;
RT "Four missense mutations identified in the protein S gene of
RT thrombosis patients with protein S deficiency: effects on secretion
RT and anticoagulant activity of protein S.";
RL Thromb. Res. 105:233-239(2002).
RN [36]
RP VARIANTS THPH5 CYS-101 AND ASN-144, AND VARIANT SER-168.
RX PubMed=12632031; DOI=10.1097/00001721-200302000-00012;
RA Boinot C., Borgel D., Kitzis A., Guicheteau M., Aiach M.,
RA Alhenc-Gelas M.;
RT "Familial thrombophilia is an oligogenetic disease: involvement of the
RT prothrombin G20210A, PROC and PROS gene mutations.";
RL Blood Coagul. Fibrinolysis 14:191-196(2003).
RN [37]
RP VARIANTS THPH5 LEU-87; TYR-121; GLU-196; HIS-355 AND LEU-667.
RX PubMed=15238143; DOI=10.1111/j.1365-2141.2004.05026.x;
RA Okada H., Takagi A., Murate T., Adachi T., Yamamoto K., Matsushita T.,
RA Takamatsu J., Sugita K., Sugimoto M., Yoshioka A., Yamazaki T.,
RA Saito H., Kojima T.;
RT "Identification of protein Salpha gene mutations including four novel
RT mutations in eight unrelated patients with protein S deficiency.";
RL Br. J. Haematol. 126:219-225(2004).
RN [38]
RP VARIANTS THPH5 ALA-67; TYR-88; GLY-129; ASN-144; PHE-175; GLY-204;
RP CYS-266; SER-267; ASP-336; ARG-357; PRO-446; PRO-515; ASP-521;
RP LYS-611; ASP-638 AND TYR-639, VARIANTS LEU-76; PRO-501; MET-559;
RP LEU-562 AND HIS-583, CHARACTERIZATION OF VARIANTS PROS1 DEFICIENCY
RP ALA-67; TYR-88; GLY-129; PHE-175; GLY-204; CYS-266; SER-267; ASP-336;
RP ARG-357; PRO-446; PRO-515; ASP-521; LYS-611; ASP-638 AND TYR-639, AND
RP CHARACTERIZATION OF VARIANTS LEU-76; LEU-562 AND HIS-583.
RX PubMed=15712227; DOI=10.1002/humu.20136;
RG Protein S Italian team (PROSIT);
RA Biguzzi E., Razzari C., Lane D.A., Castaman G., Cappellari A.,
RA Bucciarelli P., Fontana G., Margaglione M., D'Andrea G.,
RA Simmonds R.E., Rezende S.M., Preston R., Prisco D., Faioni E.M.;
RT "Molecular diversity and thrombotic risk in protein S deficiency: the
RT PROSIT study.";
RL Hum. Mutat. 25:259-269(2005).
RN [39]
RP VARIANT [LARGE SCALE ANALYSIS] GLY-545.
RX PubMed=16959974; DOI=10.1126/science.1133427;
RA Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D.,
RA Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S.,
RA Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J.,
RA Dawson D., Willson J.K.V., Gazdar A.F., Hartigan J., Wu L., Liu C.,
RA Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N.,
RA Vogelstein B., Kinzler K.W., Velculescu V.E.;
RT "The consensus coding sequences of human breast and colorectal
RT cancers.";
RL Science 314:268-274(2006).
RN [40]
RP VARIANT THPH6 CYS-234.
RX PubMed=20484936; DOI=10.1159/000298282;
RA Fischer D., Porto L., Stoll H., Geisen C., Schloesser R.L.;
RT "Intracerebral mass bleeding in a term neonate: manifestation of
RT hereditary protein S deficiency with a new mutation in the PROS1
RT gene.";
RL Neonatology 98:337-340(2010).
CC -!- FUNCTION: Anticoagulant plasma protein; it is a cofactor to
CC activated protein C in the degradation of coagulation factors Va
CC and VIIIa. It helps to prevent coagulation and stimulating
CC fibrinolysis.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- TISSUE SPECIFICITY: Plasma.
CC -!- PTM: The iron and 2-oxoglutarate dependent 3-hydroxylation of
CC aspartate and asparagine is (R) stereospecific within EGF domains
CC (By similarity).
CC -!- DISEASE: Thrombophilia due to protein S deficiency, autosomal
CC dominant (THPH5) [MIM:612336]: A hemostatic disorder characterized
CC by impaired regulation of blood coagulation and a tendency to
CC recurrent venous thrombosis. Based on the plasma levels of total
CC and free PROS1 as well as the serine protease-activated protein C
CC cofactor activity, three types of THPH5 have been described: type
CC I, characterized by reduced total and free PROS1 levels together
CC with reduced anticoagulant activity; type III, in which only free
CC PROS1 antigen and PROS1 activity levels are reduced; and the rare
CC type II which is characterized by normal concentrations of both
CC total and free PROS1 antigen, but low cofactor activity. Note=The
CC disease is caused by mutations affecting the gene represented in
CC this entry.
CC -!- DISEASE: Thrombophilia due to protein S deficiency, autosomal
CC recessive (THPH6) [MIM:614514]: A very rare and severe hematologic
CC disorder resulting in thrombosis and secondary hemorrhage usually
CC beginning in early infancy. Some affected individuals develop
CC neonatal purpura fulminans, multifocal thrombosis, or intracranial
CC hemorrhage. Note=The disease is caused by mutations affecting the
CC gene represented in this entry.
CC -!- SIMILARITY: Contains 4 EGF-like domains.
CC -!- SIMILARITY: Contains 1 Gla (gamma-carboxy-glutamate) domain.
CC -!- SIMILARITY: Contains 2 laminin G-like domains.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAP45054.1; Type=Erroneous gene model prediction;
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PROS1";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/pros1/";
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DR EMBL; Y00692; CAA68687.1; -; mRNA.
DR EMBL; Y00692; CAA68688.1; ALT_SEQ; mRNA.
DR EMBL; M15036; AAA36479.1; -; mRNA.
DR EMBL; M57853; AAA60357.1; -; Genomic_DNA.
DR EMBL; M57840; AAA60357.1; JOINED; Genomic_DNA.
DR EMBL; M57841; AAA60357.1; JOINED; Genomic_DNA.
DR EMBL; M57842; AAA60357.1; JOINED; Genomic_DNA.
DR EMBL; M57844; AAA60357.1; JOINED; Genomic_DNA.
DR EMBL; M57845; AAA60357.1; JOINED; Genomic_DNA.
DR EMBL; M57846; AAA60357.1; JOINED; Genomic_DNA.
DR EMBL; M57847; AAA60357.1; JOINED; Genomic_DNA.
DR EMBL; M57848; AAA60357.1; JOINED; Genomic_DNA.
DR EMBL; M57849; AAA60357.1; JOINED; Genomic_DNA.
DR EMBL; M57850; AAA60357.1; JOINED; Genomic_DNA.
DR EMBL; M57851; AAA60357.1; JOINED; Genomic_DNA.
DR EMBL; M57852; AAA60357.1; JOINED; Genomic_DNA.
DR EMBL; AH002948; AAA60180.1; -; Genomic_DNA.
DR EMBL; AK292994; BAF85683.1; -; mRNA.
DR EMBL; AY308744; AAP45054.1; ALT_SEQ; Genomic_DNA.
DR EMBL; CH471052; EAW79903.1; -; Genomic_DNA.
DR EMBL; CH471052; EAW79905.1; -; Genomic_DNA.
DR EMBL; BC015801; AAH15801.1; -; mRNA.
DR PIR; A35610; KXHUS.
DR RefSeq; NP_000304.2; NM_000313.3.
DR UniGene; Hs.64016; -.
DR PDB; 1Z6C; NMR; -; A=200-286.
DR PDBsum; 1Z6C; -.
DR ProteinModelPortal; P07225; -.
DR SMR; P07225; 46-86, 88-669.
DR IntAct; P07225; 3.
DR STRING; 9606.ENSP00000377783; -.
DR DrugBank; DB00025; Antihemophilic Factor.
DR DrugBank; DB00055; Drotrecogin alfa.
DR DrugBank; DB00170; Menadione.
DR PhosphoSite; P07225; -.
DR DMDM; 131086; -.
DR PaxDb; P07225; -.
DR PeptideAtlas; P07225; -.
DR PRIDE; P07225; -.
DR DNASU; 5627; -.
DR Ensembl; ENST00000394236; ENSP00000377783; ENSG00000184500.
DR GeneID; 5627; -.
DR KEGG; hsa:5627; -.
DR UCSC; uc003dqz.4; human.
DR CTD; 5627; -.
DR GeneCards; GC03M093591; -.
DR HGNC; HGNC:9456; PROS1.
DR HPA; HPA007724; -.
DR HPA; HPA023974; -.
DR MIM; 176880; gene.
DR MIM; 612336; phenotype.
DR MIM; 614514; phenotype.
DR neXtProt; NX_P07225; -.
DR Orphanet; 743; Hereditary thrombophilia due to congenital protein S deficiency.
DR PharmGKB; PA33809; -.
DR eggNOG; NOG124763; -.
DR HOGENOM; HOG000065758; -.
DR HOVERGEN; HBG051702; -.
DR InParanoid; P07225; -.
DR KO; K03908; -.
DR OMA; WNMVSVE; -.
DR OrthoDB; EOG7R2BJ0; -.
DR PhylomeDB; P07225; -.
DR Reactome; REACT_17015; Metabolism of proteins.
DR Reactome; REACT_604; Hemostasis.
DR Reactome; REACT_6900; Immune System.
DR ChiTaRS; PROS1; human.
DR EvolutionaryTrace; P07225; -.
DR GeneWiki; Protein_S; -.
DR GenomeRNAi; 5627; -.
DR NextBio; 21872; -.
DR PRO; PR:P07225; -.
DR ArrayExpress; P07225; -.
DR Bgee; P07225; -.
DR CleanEx; HS_PROS1; -.
DR Genevestigator; P07225; -.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome.
DR GO; GO:0005576; C:extracellular region; NAS:UniProtKB.
DR GO; GO:0005796; C:Golgi lumen; TAS:Reactome.
DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome.
DR GO; GO:0031093; C:platelet alpha granule lumen; TAS:Reactome.
DR GO; GO:0005509; F:calcium ion binding; IEA:InterPro.
DR GO; GO:0004866; F:endopeptidase inhibitor activity; TAS:ProtInc.
DR GO; GO:0042730; P:fibrinolysis; IEA:UniProtKB-KW.
DR GO; GO:0045087; P:innate immune response; TAS:Reactome.
DR GO; GO:0050900; P:leukocyte migration; TAS:Reactome.
DR GO; GO:0017187; P:peptidyl-glutamic acid carboxylation; TAS:Reactome.
DR GO; GO:0030168; P:platelet activation; TAS:Reactome.
DR GO; GO:0002576; P:platelet degranulation; TAS:Reactome.
DR GO; GO:0043687; P:post-translational protein modification; TAS:Reactome.
DR GO; GO:0006508; P:proteolysis; TAS:Reactome.
DR GO; GO:0030449; P:regulation of complement activation; TAS:Reactome.
DR Gene3D; 2.60.120.200; -; 2.
DR Gene3D; 4.10.740.10; -; 1.
DR InterPro; IPR017857; Coagulation_fac_subgr_Gla_dom.
DR InterPro; IPR008985; ConA-like_lec_gl_sf.
DR InterPro; IPR013320; ConA-like_subgrp.
DR InterPro; IPR000742; EG-like_dom.
DR InterPro; IPR001881; EGF-like_Ca-bd_dom.
DR InterPro; IPR013032; EGF-like_CS.
DR InterPro; IPR000152; EGF-type_Asp/Asn_hydroxyl_site.
DR InterPro; IPR018097; EGF_Ca-bd_CS.
DR InterPro; IPR000294; GLA_domain.
DR InterPro; IPR009030; Growth_fac_rcpt_N_dom.
DR InterPro; IPR001791; Laminin_G.
DR Pfam; PF00008; EGF; 1.
DR Pfam; PF07645; EGF_CA; 1.
DR Pfam; PF00594; Gla; 1.
DR Pfam; PF00054; Laminin_G_1; 1.
DR Pfam; PF02210; Laminin_G_2; 1.
DR PRINTS; PR00001; GLABLOOD.
DR SMART; SM00181; EGF; 1.
DR SMART; SM00179; EGF_CA; 3.
DR SMART; SM00069; GLA; 1.
DR SMART; SM00282; LamG; 2.
DR SUPFAM; SSF49899; SSF49899; 2.
DR SUPFAM; SSF57184; SSF57184; 1.
DR SUPFAM; SSF57630; SSF57630; 1.
DR PROSITE; PS00010; ASX_HYDROXYL; 4.
DR PROSITE; PS00022; EGF_1; 1.
DR PROSITE; PS01186; EGF_2; 3.
DR PROSITE; PS50026; EGF_3; 4.
DR PROSITE; PS01187; EGF_CA; 3.
DR PROSITE; PS00011; GLA_1; 1.
DR PROSITE; PS50998; GLA_2; 1.
DR PROSITE; PS50025; LAM_G_DOMAIN; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Blood coagulation; Calcium;
KW Cleavage on pair of basic residues; Complete proteome;
KW Disease mutation; Disulfide bond; EGF-like domain; Fibrinolysis;
KW Gamma-carboxyglutamic acid; Glycoprotein; Hemostasis; Hydroxylation;
KW Polymorphism; Reference proteome; Repeat; Secreted; Signal;
KW Thrombophilia; Zymogen.
FT SIGNAL 1 24
FT PROPEP 25 41
FT /FTId=PRO_0000022119.
FT CHAIN 42 676 Vitamin K-dependent protein S.
FT /FTId=PRO_0000022120.
FT DOMAIN 42 87 Gla.
FT DOMAIN 117 155 EGF-like 1.
FT DOMAIN 157 200 EGF-like 2; calcium-binding (Potential).
FT DOMAIN 201 242 EGF-like 3; calcium-binding (Potential).
FT DOMAIN 243 283 EGF-like 4; calcium-binding (Potential).
FT DOMAIN 299 475 Laminin G-like 1.
FT DOMAIN 484 666 Laminin G-like 2.
FT REGION 88 116 Thrombin-sensitive.
FT SITE 499 499 Not glycosylated; in variant Heerlen.
FT MOD_RES 47 47 4-carboxyglutamate.
FT MOD_RES 48 48 4-carboxyglutamate.
FT MOD_RES 55 55 4-carboxyglutamate.
FT MOD_RES 57 57 4-carboxyglutamate.
FT MOD_RES 60 60 4-carboxyglutamate.
FT MOD_RES 61 61 4-carboxyglutamate.
FT MOD_RES 66 66 4-carboxyglutamate.
FT MOD_RES 67 67 4-carboxyglutamate.
FT MOD_RES 70 70 4-carboxyglutamate.
FT MOD_RES 73 73 4-carboxyglutamate.
FT MOD_RES 77 77 4-carboxyglutamate.
FT MOD_RES 136 136 (3R)-3-hydroxyaspartate (By similarity).
FT CARBOHYD 499 499 N-linked (GlcNAc...).
FT CARBOHYD 509 509 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 530 530 N-linked (GlcNAc...).
FT DISULFID 58 63 By similarity.
FT DISULFID 121 134 By similarity.
FT DISULFID 126 143 By similarity.
FT DISULFID 145 154 By similarity.
FT DISULFID 161 175 By similarity.
FT DISULFID 171 184 By similarity.
FT DISULFID 186 199 By similarity.
FT DISULFID 205 217
FT DISULFID 212 226
FT DISULFID 228 241
FT DISULFID 247 256
FT DISULFID 252 265
FT DISULFID 267 282
FT DISULFID 449 475 By similarity.
FT DISULFID 639 666 By similarity.
FT VARIANT 15 15 L -> H (in THPH5).
FT /FTId=VAR_046802.
FT VARIANT 18 18 V -> E (in THPH5; expresses very low/
FT undetectable PROS1 levels compared to
FT wild-type; has impaired secretion;
FT intracellular degradation of unsecreted
FT material is found).
FT /FTId=VAR_046803.
FT VARIANT 40 40 R -> L (in THPH5; dbSNP:rs7614835).
FT /FTId=VAR_046804.
FT VARIANT 41 41 R -> H (in THPH5).
FT /FTId=VAR_046805.
FT VARIANT 50 50 K -> E (in THPH5).
FT /FTId=VAR_046806.
FT VARIANT 52 52 G -> D (in THPH5; does not affect PROS1
FT production but results in 15.2-fold
FT reduced PROS1 activity; has 5.4 fold
FT reduced affinity for anionic phospholipid
FT vesicles (P < 0.0001) and decreased
FT affinity for an antibody specific for the
FT Ca(2+)-dependent conformation of the
FT PROS1 Gla domain).
FT /FTId=VAR_046807.
FT VARIANT 67 67 E -> A (in THPH5).
FT /FTId=VAR_046808.
FT VARIANT 68 68 A -> D (in THPH5).
FT /FTId=VAR_046809.
FT VARIANT 72 72 F -> C (in THPH5).
FT /FTId=VAR_046810.
FT VARIANT 76 76 P -> L (in dbSNP:rs73846070).
FT /FTId=VAR_046811.
FT VARIANT 78 78 T -> M (in THPH5; reduces expression of
FT PROS1 by 33.2% (P < 0.001) and activity
FT by 3.6-fold; has only a modest 1.5-fold
FT (P < 0.001) reduced affinity for
FT phospholipid and an antibody specific for
FT the Ca(2+)-dependent conformation of the
FT PROS1 Gla domain; dbSNP:rs6122).
FT /FTId=VAR_014666.
FT VARIANT 87 87 V -> L (in THPH5).
FT /FTId=VAR_046812.
FT VARIANT 88 88 C -> Y (in THPH5).
FT /FTId=VAR_046813.
FT VARIANT 90 90 R -> C (in THPH5; produces around 50% of
FT PROS1 levels compared to wild-type; has
FT impaired secretion; intracellular
FT degradation of unsecreted material is
FT found).
FT /FTId=VAR_046814.
FT VARIANT 90 90 R -> H (in THPH5).
FT /FTId=VAR_046815.
FT VARIANT 95 95 G -> E (in THPH5).
FT /FTId=VAR_046816.
FT VARIANT 95 95 G -> R (in THPH5; the activated protein
FT cofactor activity is inhibited by C4BPB
FT with a dose dependency similar to that of
FT wild-type PROS1).
FT /FTId=VAR_046817.
FT VARIANT 98 98 T -> S (in dbSNP:rs142805170).
FT /FTId=VAR_046818.
FT VARIANT 101 101 R -> C (in THPH5).
FT /FTId=VAR_046819.
FT VARIANT 111 111 R -> S (in THPH5).
FT /FTId=VAR_046820.
FT VARIANT 121 121 C -> Y (in THPH5).
FT /FTId=VAR_046821.
FT VARIANT 129 129 D -> G (in THPH5).
FT /FTId=VAR_046822.
FT VARIANT 144 144 T -> N (in THPH5).
FT /FTId=VAR_046823.
FT VARIANT 149 149 W -> C (in THPH5).
FT /FTId=VAR_046824.
FT VARIANT 157 157 D -> G (in THPH5).
FT /FTId=VAR_046825.
FT VARIANT 161 161 C -> G (in THPH5).
FT /FTId=VAR_046826.
FT VARIANT 166 166 N -> Y (in THPH5).
FT /FTId=VAR_046827.
FT VARIANT 168 168 N -> S.
FT /FTId=VAR_046828.
FT VARIANT 175 175 C -> F (in THPH5).
FT /FTId=VAR_046829.
FT VARIANT 186 186 C -> Y (in THPH5).
FT /FTId=VAR_046830.
FT VARIANT 196 196 K -> E (in THPH5; Tokushima; the specific
FT activity decreases to 58% of that of the
FT wild-type PROS1; the activated protein
FT cofactor activity is inhibited by C4BPB
FT with a dose dependency similar to that of
FT wild-type PROS1; dbSNP:rs121918474).
FT /FTId=VAR_005566.
FT VARIANT 204 204 E -> G (in THPH5).
FT /FTId=VAR_046831.
FT VARIANT 233 233 R -> K (in THPH5; expresses lower (p <
FT 0.05) PROS1 levels compared to wild-type;
FT has impaired secretion;
FT dbSNP:rs41267007).
FT /FTId=VAR_046832.
FT VARIANT 234 234 Y -> C (in THPH6).
FT /FTId=VAR_067302.
FT VARIANT 241 241 C -> S (in THPH5).
FT /FTId=VAR_046833.
FT VARIANT 243 243 D -> N (in THPH5).
FT /FTId=VAR_046834.
FT VARIANT 245 245 D -> G (in THPH5).
FT /FTId=VAR_046835.
FT VARIANT 247 247 C -> G (in THPH5).
FT /FTId=VAR_046836.
FT VARIANT 249 249 E -> K (in THPH5).
FT /FTId=VAR_046837.
FT VARIANT 258 258 N -> S (in THPH5; produces around 30% of
FT PROS1 levels compared to wild-type; has
FT impaired secretion; intracellular
FT degradation of unsecreted material is
FT found).
FT /FTId=VAR_005567.
FT VARIANT 265 265 C -> R (in THPH5).
FT /FTId=VAR_046838.
FT VARIANT 265 265 C -> W (in THPH5).
FT /FTId=VAR_046839.
FT VARIANT 266 266 Y -> C (in THPH5).
FT /FTId=VAR_046840.
FT VARIANT 267 267 C -> S (in THPH5).
FT /FTId=VAR_046841.
FT VARIANT 300 300 L -> P (in THPH5).
FT /FTId=VAR_046842.
FT VARIANT 324 324 S -> P (in THPH5).
FT /FTId=VAR_046843.
FT VARIANT 336 336 G -> D (in THPH5).
FT /FTId=VAR_046844.
FT VARIANT 336 336 G -> S (in THPH5).
FT /FTId=VAR_046845.
FT VARIANT 336 336 G -> V (in THPH5; expresses very low/
FT undetectable PROS1 levels compared to
FT wild-type; has impaired secretion;
FT intracellular degradation of unsecreted
FT material is found).
FT /FTId=VAR_046846.
FT VARIANT 339 339 L -> P (in THPH5).
FT /FTId=VAR_046847.
FT VARIANT 351 351 L -> P (in THPH5).
FT /FTId=VAR_046848.
FT VARIANT 355 355 R -> H (in THPH5).
FT /FTId=VAR_046849.
FT VARIANT 357 357 G -> R (in THPH5).
FT /FTId=VAR_046850.
FT VARIANT 364 364 K -> E (in THPH5).
FT /FTId=VAR_046851.
FT VARIANT 376 376 D -> N (in THPH5).
FT /FTId=VAR_046852.
FT VARIANT 381 381 G -> D (in THPH5).
FT /FTId=VAR_046853.
FT VARIANT 381 381 G -> V (in THPH5).
FT /FTId=VAR_046854.
FT VARIANT 383 383 W -> R (in THPH5).
FT /FTId=VAR_046855.
FT VARIANT 385 385 M -> V.
FT /FTId=VAR_046856.
FT VARIANT 390 390 E -> K (in THPH5).
FT /FTId=VAR_046857.
FT VARIANT 446 446 L -> P (in THPH5).
FT /FTId=VAR_046858.
FT VARIANT 449 449 C -> S (in THPH5).
FT /FTId=VAR_046859.
FT VARIANT 475 475 C -> R (in THPH5).
FT /FTId=VAR_046860.
FT VARIANT 482 482 G -> C (in THPH5).
FT /FTId=VAR_014116.
FT VARIANT 485 485 Y -> C (in THPH5).
FT /FTId=VAR_014117.
FT VARIANT 495 495 I -> V (in dbSNP:rs5017712).
FT /FTId=VAR_046861.
FT VARIANT 501 501 S -> A (in THPH5; dbSNP:rs121918472).
FT /FTId=VAR_046862.
FT VARIANT 501 501 S -> P (variant Heerlen; could be
FT associated with THPH5;
FT dbSNP:rs121918472).
FT /FTId=VAR_005568.
FT VARIANT 508 508 V -> G (in THPH5).
FT /FTId=VAR_046863.
FT VARIANT 508 508 V -> M (in THPH5).
FT /FTId=VAR_046864.
FT VARIANT 515 515 R -> C (in THPH5; secretion of the mutant
FT markedly decreased compared with that of
FT the wild-type; intracellular degradation
FT and impaired secretion of the mutant).
FT /FTId=VAR_046865.
FT VARIANT 515 515 R -> P (in THPH5).
FT /FTId=VAR_046866.
FT VARIANT 521 521 G -> D (in THPH5).
FT /FTId=VAR_046867.
FT VARIANT 525 525 A -> P (in THPH5).
FT /FTId=VAR_046868.
FT VARIANT 526 526 L -> S (in THPH5).
FT /FTId=VAR_046869.
FT VARIANT 532 532 T -> A (in THPH5).
FT /FTId=VAR_046870.
FT VARIANT 545 545 E -> G (in a colorectal cancer sample;
FT somatic mutation).
FT /FTId=VAR_035981.
FT VARIANT 552 552 L -> S (in THPH5).
FT /FTId=VAR_046871.
FT VARIANT 559 559 I -> M (in dbSNP:rs184798444).
FT /FTId=VAR_014118.
FT VARIANT 561 561 R -> G (in THPH5).
FT /FTId=VAR_014119.
FT VARIANT 562 562 I -> L (in THPH5; unknown pathological
FT significance).
FT /FTId=VAR_046872.
FT VARIANT 568 568 C -> Y (in THPH5).
FT /FTId=VAR_046873.
FT VARIANT 575 575 L -> R (in THPH5).
FT /FTId=VAR_046874.
FT VARIANT 583 583 N -> H.
FT /FTId=VAR_046875.
FT VARIANT 584 584 L -> Q (in THPH5).
FT /FTId=VAR_046876.
FT VARIANT 611 611 M -> K (in THPH5).
FT /FTId=VAR_046877.
FT VARIANT 611 611 M -> T (in THPH5).
FT /FTId=VAR_046878.
FT VARIANT 616 616 A -> P (in THPH5).
FT /FTId=VAR_046879.
FT VARIANT 622 622 L -> R (in THPH5).
FT /FTId=VAR_046880.
FT VARIANT 630 630 T -> I (in THPH5; the activated protein
FT cofactor activity is inhibited by C4BPB
FT with a dose dependency similar to that of
FT wild-type PROS1).
FT /FTId=VAR_046881.
FT VARIANT 636 636 Y -> C (in THPH5; shows intracellular
FT degradation and decreased secretion).
FT /FTId=VAR_046882.
FT VARIANT 638 638 G -> D (in THPH5).
FT /FTId=VAR_046883.
FT VARIANT 639 639 C -> F (in THPH5).
FT /FTId=VAR_046884.
FT VARIANT 639 639 C -> Y (in THPH5).
FT /FTId=VAR_046885.
FT VARIANT 640 640 M -> T (in THPH5).
FT /FTId=VAR_046886.
FT VARIANT 644 644 I -> S (in THPH5).
FT /FTId=VAR_046887.
FT VARIANT 664 664 H -> P (in THPH5; expresses very low/
FT undetectable PROS1 levels compared to
FT wild-type; has impaired secretion;
FT intracellular degradation of unsecreted
FT material is found).
FT /FTId=VAR_046888.
FT VARIANT 665 665 S -> L (in THPH5).
FT /FTId=VAR_046889.
FT VARIANT 666 666 C -> R (in THPH5).
FT /FTId=VAR_046890.
FT VARIANT 667 667 P -> L (in THPH5).
FT /FTId=VAR_046891.
FT MUTAGEN 515 515 R->A,E: Markedly reduced secretion of the
FT mutant.
FT MUTAGEN 515 515 R->K: No change in secretion of the
FT mutant.
FT CONFLICT 11 11 L -> P (in Ref. 2; AAA36479).
FT CONFLICT 26 26 F -> L (in Ref. 2; AAA36479).
FT STRAND 204 212
FT STRAND 227 229
FT STRAND 233 235
FT TURN 236 239
FT STRAND 240 242
FT HELIX 246 249
FT STRAND 253 256
FT STRAND 260 262
FT STRAND 269 271
FT STRAND 279 281
SQ SEQUENCE 676 AA; 75123 MW; 2B88A04F85403F25 CRC64;
MRVLGGRCGA LLACLLLVLP VSEANFLSKQ QASQVLVRKR RANSLLEETK QGNLERECIE
ELCNKEEARE VFENDPETDY FYPKYLVCLR SFQTGLFTAA RQSTNAYPDL RSCVNAIPDQ
CSPLPCNEDG YMSCKDGKAS FTCTCKPGWQ GEKCEFDINE CKDPSNINGG CSQICDNTPG
SYHCSCKNGF VMLSNKKDCK DVDECSLKPS ICGTAVCKNI PGDFECECPE GYRYNLKSKS
CEDIDECSEN MCAQLCVNYP GGYTCYCDGK KGFKLAQDQK SCEVVSVCLP LNLDTKYELL
YLAEQFAGVV LYLKFRLPEI SRFSAEFDFR TYDSEGVILY AESIDHSAWL LIALRGGKIE
VQLKNEHTSK ITTGGDVINN GLWNMVSVEE LEHSISIKIA KEAVMDINKP GPLFKPENGL
LETKVYFAGF PRKVESELIK PINPRLDGCI RSWNLMKQGA SGIKEIIQEK QNKHCLVTVE
KGSYYPGSGI AQFHIDYNNV SSAEGWHVNV TLNIRPSTGT GVMLALVSGN NTVPFAVSLV
DSTSEKSQDI LLSVENTVIY RIQALSLCSD QQSHLEFRVN RNNLELSTPL KIETISHEDL
QRQLAVLDKA MKAKVATYLG GLPDVPFSAT PVNAFYNGCM EVNINGVQLD LDEAISKHND
IRAHSCPSVW KKTKNS
//

MIM 176880
*RECORD*
*FIELD* NO
176880
*FIELD* TI
*176880 PROTEIN S; PROS1
;;PROTEIN S, ALPHA; PSA
PROTEIN S PSEUDOGENE, INCLUDED; PROSP, INCLUDED;;
read morePROTEIN S, BETA, INCLUDED; PSB, INCLUDED;;
PROS2, INCLUDED
*FIELD* TX

DESCRIPTION

Protein S is a vitamin K-dependent plasma protein that inhibits blood
clotting by serving as a nonenzymatic cofactor for activated protein C
(PROC; 612283) in the inactivation of procoagulant factors V (F5;
612309) and VIII (F8; 300841). Protein S exists in 2 forms in plasma:
the free, functionally active form, and the inactive form complexed with
C4b-binding protein (C4BPA; 120830) (Dahlback and Stenflo, 1981).

CLONING

Lundwall et al. (1986) isolated and sequenced cDNA clones for protein S.
Human protein S is a single-chain protein of 635 amino acids with 82%
homology to bovine protein S. Hoskins et al. (1987) isolated cDNA for a
protein S precursor.

Edenbrandt et al. (1990) isolated clones corresponding to the 3-prime
part of the PROS1 gene, including the thrombin (F2; 176930)-sensitive
region, 4 domains that are homologous to the epidermal growth factor
(EGF; 131530) precursor, the COOH-terminal part of protein S that is
homologous to a plasma sex hormone binding globulin (SHBG; 182205), and
the 3-prime untranslated region.

GENE FUNCTION

In human plasma, around 40% of protein S circulates as a free protein,
while the remaining 60% forms a noncovalent 1:1 stoichiometric complex
with the beta-chain of the complement C4b-binding protein (C4BPB;
120831) (Dahlback, 1991). This interaction is of high affinity and
abolishes the anticoagulant properties of protein S. Therefore, in
plasma, only the molar excess of protein S over C4BPB circulates in a
free form and is active as a cofactor of activated protein C (APC) in
the inactivation of the procoagulant factors Va and VIIIa (Griffin et
al., 1992).

Maillard et al. (1992) studied protein S synthesis and secretion by
human osteosarcoma cell lines and by normal adult human osteoblast-like
cells. They showed that protein S is synthesized by osteoblasts in an
active form and incorporated in the mineralized matrix of bone.
Previously, protein S was known to be synthesized mostly by hepatocytes.

Heeb et al. (1994) presented data that demonstrated mechanisms of
anticoagulant action for protein S that are independent of activated
protein C and that involve direct binding to factors Xa and Va and
direct inhibition of factor Xa.

Anderson et al. (2003) identified protein S as the factor in serum that
mediates serum-stimulated macrophage phagocytosis of apoptotic cells, a
process thought to limit the development of inflammation and autoimmune
disease. Flow cytometric and competitive inhibition analyses
demonstrated that protein S binds exclusively to
phosphatidylserine-positive apoptotic cells in a calcium-dependent
manner. Anderson et al. (2003) concluded that protein S is a
multifunctional protein that facilitates the clearance of early
apoptotic cells in addition to regulating blood coagulation.

GENE STRUCTURE

Schmidel et al. (1990) determined that the PROS1 gene contains 15 exons
and spans more than 80 kb.

MAPPING

By Southern blot analysis of DNA from somatic cell hybrids, Naylor et
al. (1987) and Long et al. (1988) assigned the protein S gene to
chromosome 3p21-q21. By study of somatic cell hybrids with cDNA probes,
including hybrids with rearranged chromosomes, Watkins et al. (1987,
1988) assigned the protein S gene to 3p21-q21; see Stanislovitis et al.
(1987).

By in situ hybridization, Watkins et al. (1988) assigned the PROS gene
to chromosome 3p11.1-q11.2, the region immediately surrounding the
centromere.

Hartz (2008) mapped the PROS1 gene to chromosome 3q11.2 based on an
alignment of the PROS1 sequence (GenBank GENBANK AK292994) with the
genomic sequence (build 36.1).

- Pseudogene

By Southern analysis of the protein S locus, with cDNA probes
encompassing the 3-prime untranslated region of protein S mRNA, Ploos
van Amstel et al. (1987) determined that there are 2 protein S genes,
both situated on chromosome 3. Conservation of restriction sites
suggested that the 2 genes are highly homologous.

Ploos van Amstel et al. (1988) reported the nucleotide sequence of the
complete 3-prime untranslated regions of the 2 protein S genes, which
they designated PS-alpha (PSA) and PS-beta (PSB). Comparison of the 2
genes with the reported protein S liver cDNAs showed that the latter all
originated from the PSA gene. Therefore, PSA appeared to be the major
locus for synthesis of liver protein S mRNA.

Edenbrandt et al. (1990) isolated and mapped genomic clones
corresponding to the protein S beta-gene, which was found to contain
stop codons and a 2 bp-deletion introducing a frameshift, suggesting
that it is a pseudogene.

The protein S beta locus represents a pseudogene (PROSP) on chromosome
3.

MOLECULAR GENETICS

- Autosomal Dominant Thrombophilia due to Protein S Deficiency

Ploos van Amstel et al. (1989) used Southern blot analysis to identify a
heterozygous deletion in the PROS1 gene in a patient with familial
thrombophilia associated with protein S deficiency (THPH5; 612336). The
deletion segregated with the disorder in this family. The findings
indicated that this specific disorder is directly the result of a defect
in the protein S gene.

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.

Beauchamp et al. (2004) stated that over 200 mutations in the PROS1 gene
had been identified in patients with protein S deficiency.

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. Three probands with CNV
had positive family history and the CNV cosegregated with protein S
deficiency in family members.

- Autosomal Recessive Thrombophilia due to Protein S Deficiency

In a Thai infant with autosomal recessive thrombophilia due to protein S
deficiency (THPH6; 614514) (Mahasandana et al., 1990), Pung-amritt et
al. (1999) identified compound heterozygosity for 2 mutations in the
PROS1 gene (176880.0010 and 176880.0011). The patient presented with
neonatal purpura fulminans. Each parent, who was found by ELISA studies
to have about 50% of protein S free antigen, was heterozygous for 1 of
the mutations.

In an infant, born of Albanian parents, with autosomal recessive
thrombophilia due to protein S deficiency, Fischer et al. (2010)
identified a homozygous mutation in the PROS1 gene (176880.0012). The
patient presented with seizures and hemorrhagic shock associated with a
massive intracranial bleed and laboratory evidence of disseminated
intravascular coagulation. After stabilization, laboratory studies
showed thrombophilia due to severe protein S deficiency (less than 10%).
Each parent was heterozygous for the mutation and showed about 50%
protein S activity.

ANIMAL MODEL

Burstyn-Cohen et al. (2009) generated several lines of transgenic mice
with conditional knockout of the Pros1 gene in (1) all cells, (2) in
hepatocytes, (3) in endothelial and hematopoietic cells, and (4) in
vascular smooth muscle cells. Complete knockout of Pros1 in all cells
was embryonic lethal. Pros1 -/- mice died between E15.5 and E17.5 from
massive coagulopathy with large blood clots and associated hemorrhage
throughout the body. The embryonic vasculature of Pros1 -/- mice showed
defects in vessel development, integrity, and function, with reduction
of smooth muscle staining. Pros1 +/- mice showed milder defects in
vessel morphology, with permeability defects, and also showed shorter
clot times than wildtype, consistent with a prothrombotic state.
However, this effect was independent of protein C, suggesting that
protein S can inhibit clotting on its own. Vascular smooth
muscle-specific Pros1 -/- mice showed mild defects similar to Pros1 +/-
mice. Hepatocyte-specific Pros1 -/- mice were viable and had normal
vessel morphology, although about 15% showed focal fibrin deposition in
blood vessels. Vascular endothelial and hematopoietic cell-specific
Pros1 -/- mice were also viable, but had vessel defects. They also had
approximately 57% circulating protein S compared to wildtype, indicating
that these cells contribute to circulating protein S levels.
Burstyn-Cohen et al. (2009) suggested that PROS1 may have a direct
anticoagulant function in the blood coagulation cascade as well as a
role in vascular development and function, most likely via its ability
to bind to and activate TAM receptors, such as AXL (109135).

Saller et al. (2009) found that Pros -/- embryos died late in gestation
with consumptive coagulopathy. Pros +/- mice were viable and appeared
normal, and they did not present abnormal mortality or signs of
thrombosis with age. Pros +/- blood cell counts and plasma levels of
coagulation factors were normal, although plasma protein S concentration
was half normal. However, Pros +/- mice exhibited reduced plasma
activated protein C cofactor (F5) activity, reduced anticoagulant
activity, and increased sensitivity to development of tissue factor (F3;
134390)-induced thromboembolism.

*FIELD* AV
.0001
PROTEIN S HEERLEN
PROS1, SER460PRO

Bertina et al. (1990) reported an abnormal protein S that had a slightly
lower molecular weight than normal, bound normally to C4BP (120830), and
retained full APC-cofactor activity. DNA analysis showed that the
abnormality resulted from a T-to-C transition in the PROS1 gene,
resulting in a ser460-to-pro (S460P) substitution within a potential
glycosylation site. The variant was considered to be a neutral
polymorphism and was estimated to be in 0.52% of healthy blood donors.
Bertina et al. (1990) suggested that this variant, termed the 'Heerlen
variant,' may be identical with the variant reported by Schwarz et al.
(1989).

Beauchamp et al. (2004) studied the molecular basis of free protein S
deficiency in 7 individuals identified with persistently low plasma
protein S levels from a survey of 3,788 Scottish blood donors. Five of
the donors were found to be heterozygous for the Heerlen polymorphism.
Haplotype analysis indicated a founder effect in 4 of the 5 donors.
Beauchamp et al. (2004) estimated the prevalence of heritable protein S
deficiency in the Scottish population to be between 0.16 and 0.21%,
predominantly resulting from the presence of the Heerlen allele.
Although all had persistently decreased free protein S, thrombotic
events were not reported.

.0002
THROMBOPHILIA DUE TO PROTEIN S DEFICIENCY, AUTOSOMAL DOMINANT
PROS1, ASN217SER

In affected members of a family with protein S deficiency (612336),
Formstone et al. (1995) identified a heterozygous A-to-G transition in
exon 8 of the PROS gene, resulting in an asn217-to-ser (N217S)
substitution in the fourth EGF domain of protein S.

.0003
THROMBOPHILIA DUE TO PROTEIN S DEFICIENCY, AUTOSOMAL DOMINANT
PROS1, LYS155GLU

In a 29-year-old woman with thrombotic disease associated with
heterozygous protein S deficiency (612336), Hayashi et al. (1994)
identified a heterozygous A-to-G transition in exon 6 of the PROS1 gene,
resulting in a lys155-to-glu (K155E) substitution in the second
epidermal growth factor-like domain. The patient had normal levels of
both total and free protein S antigen, but low cofactor activity for
activated protein C, indicating that she had a variant of protein S,
referred to as protein S Tokushima. Approximately one-half of the
patient's protein S appeared to be the variant with a higher molecular
weight than normal. The patient's mother and a maternal aunt also had
thrombotic disease. The disorder in this family was classified as type
IIb protein S deficiency.

.0004
THROMBOPHILIA DUE TO PROTEIN S DEFICIENCY, AUTOSOMAL DOMINANT
PROS1, IVS10DS, G-A, +5

In 2 unrelated individuals with thrombophilia associated with protein S
deficiency (612336), Reitsma et al. (1994) identified a heterozygous
G-to-A transition at position +5 of the donor splice site consensus
sequence of intron 10 of the PROS1 gene.

.0005
THROMBOPHILIA DUE TO PROTEIN S DEFICIENCY, AUTOSOMAL DOMINANT
PROS1, TER636TYR, 649TER

In 2 unrelated probands with thrombophilia associated with protein S
deficiency (612336), Reitsma et al. (1994) identified a heterozygous
A-to-T transversion at the wobble position of the stop codon of the
PROS1 gene. This led to extension of the normal protein S molecule with
14 amino acids before a novel stop codon was reached. Stop codon 636 was
converted to tyr by the A-to-T mutation; the new stop was at codon 649.

.0006
THROMBOPHILIA DUE TO PROTEIN S DEFICIENCY, AUTOSOMAL DOMINANT
PROS1, IVS11AS, A-G, -9

In affected individuals of 7 kindreds with thrombophilia associated with
protein S deficiency (612336), Beauchamp et al. (1998) identified a
heterozygous A-to-G transition 9 bp upstream of exon 12 in intron 11 of
the PROS1 gene. In all but 1 case, the mutation caused type I
deficiency; 1 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 that the mutation created a new RNA acceptor site introducing
8 nucleotides of intronic sequence into the mature mRNA. Haplotype
analysis of a defective PROS1 allele in 6 families revealed the same
haplotype in all affected individuals, suggesting the existence of a
common ancestor. Six of the 14 relatives with the mutation experienced
at least 1 venous thrombotic event, strongly supporting the association
of the mutation with venous thrombosis.

.0007
THROMBOPHILIA DUE TO PROTEIN S DEFICIENCY, AUTOSOMAL DOMINANT
PROS1, GLN238TER

In affected members of 4 families with protein S deficiency (612336),
Espinosa-Parrilla et al. (1999) identified a heterozygous 981C-T
transition in exon 8 of the PROS1 gene, resulting in a gln238-to-ter
(Q238X) substitution.

.0008
THROMBOPHILIA DUE TO PROTEIN S DEFICIENCY, AUTOSOMAL DOMINANT
PROS1, ARG520GLY

In affected members of a family with protein S deficiency (612336),
Espinosa-Parrilla et al. (1999) identified a heterozygous 1827C-G
transversion in exon 14 of the PROS1 gene, resulting in an arg520-to-gly
(R520G) substitution.

.0009
THROMBOPHILIA DUE TO PROTEIN S DEFICIENCY, AUTOSOMAL DOMINANT
PROS1, ARG355CYS

In affected members of a 3-generation Chinese family with autosomal
dominant protein S deficiency (612336), Leung et al. (2010) identified a
heterozygous 1063C-T transition in exon 10 of the PROS1 gene, resulting
in an arg355-to-cys (R355C) substitution in the first globular domain of
protein S. Three individuals with the mutation were symptomatic and had
onset of ischemic stroke in their forties. Three additional family
members with the mutation 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.

.0010
THROMBOPHILIA DUE TO PROTEIN S DEFICIENCY, AUTOSOMAL RECESSIVE
PROS1, 1-BP INS, 146A

In a Thai infant with autosomal recessive thrombophilia due to protein S
deficiency (THPH6; 614514), Pung-amritt et al. (1999) identified
compound heterozygosity for 2 mutations in the PROS1 gene: a 1-bp
insertion in exon 6 (146insA), resulting in a frameshift and premature
truncation at residue 155, and a C-to-T transition in exon 12, resulting
in an arg410-to-ter (R410X; 176880.0011) substitution. Each parent, who
had about 50% of protein S free antigen, was heterozygous for 1 of the
mutations. The patient, who was first reported by Mahasandana et al.
(1990), presented at age 10 days with neonatal purpura fulminans and
later developed disseminated intravascular coagulation, which responded
to cryoprecipitate transfusion. She was found to have endophthalmitis
and was blind, suggesting retinal vessel thrombosis in utero. Protein S
was almost undetectable in the patient's plasma. The family history was
negative for thrombosis.

.0011
THROMBOPHILIA DUE TO PROTEIN S DEFICIENCY, AUTOSOMAL RECESSIVE
PROS1, ARG410TER

See 176880.0010 and Pung-amritt et al. (1999).

.0012
THROMBOPHILIA DUE TO PROTEIN S DEFICIENCY, AUTOSOMAL RECESSIVE
PROS1, TYR234CYS

In an infant, born of Albanian parents, with autosomal recessive
thrombophilia due to protein S deficiency (614514), Fischer et al.
(2010) identified a homozygous 701A-G transition in the PROS1 gene,
resulting in a tyr234-to-cys (Y234C) substitution. The patient presented
on the fourth day of life with seizures and hemorrhagic shock associated
with a massive intracranial bleed and laboratory evidence of
disseminated intravascular coagulation. After stabilization, laboratory
studies showed thrombophilia due to severe protein S deficiency (less
than 10% activity). The infant later developed acute arterial thrombosis
of the aorta and died on the eighth day of life. Postmortem examination
showed diffuse thromboses of intracerebral capillaries, suggesting that
the underlying prothrombotic condition resulted in hemorrhage. Each
parent was heterozygous for the mutation and showed about 50% protein S
activity.

*FIELD* RF
1. Anderson, H. A.; Maylock, C. A.; Williams, J. A.; Paweletz, C.
P.; Shu, H.; Shacter, E.: Serum-derived protein S binds to phosphatidylserine
and stimulates the phagocytosis of apoptotic cells. Nature Immun. 4:
87-91, 2003.

2. Beauchamp, N. J.; Daly, M. E.; Makris, M.; Preston, F. E.; Peake,
I. R.: 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. 79: 1086-1091, 1998.

3. Beauchamp, N. J.; Dykes, A. C.; Parikh, N.; Tait, R. C.; Daly,
M. E.: The prevalence of, and molecular defects underlying, inherited
protein S deficiency in the general population. Brit. J. Haemat. 125:
647-654, 2004.

4. Bertina, R. M.; Ploos van Amstel, H. K.; van Wijngaarden, A.; Coenen,
J.; Leemhuis, M. P.; Deutz-Terlouw, P. P.; van der Linden, I. K.;
Reitsma, P. H.: Heerlen polymorphism of protein S, an immunologic
polymorphism due to dimorphism of residue 460. Blood 76: 538-548,
1990.

5. Burstyn-Cohen, T.; Heeb, M. J.; Lemke, G.: Lack of protein S in
mice causes embryonic lethal coagulopathy and vascular dysgenesis. J.
Clin. Invest. 119: 2942-2953, 2009.

6. Dahlback, B.: Protein S and C4b-binding protein: components involved
in the regulation of the protein C anticoagulant system. Thromb.
Haemost. 66: 49-61, 1991.

7. Dahlback, B.; Stenflo, J.: High molecular weight complex in human
plasma between vitamin K dependent protein S and complement component
C4b-binding protein. Proc. Nat. Acad. Sci. 78: 2512-2516, 1981.

8. Edenbrandt, C.-M.; Lundwall, A.; Sydro, R.; Stenflo, J.: Molecular
analysis of the gene for vitamin K dependent protein S and its pseudogene:
cloning and partial gene organization. Biochemistry 29: 7861-7868,
1990.

9. 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.

10. Fischer, D.; Porto, L.; Stoll, H.; Geisen, C.; Schloesser, R.
L.: Intracerebral mass bleeding in a term neonate: manifestation
of hereditary protein S deficiency with a new mutation in the PROS1
gene. Neonatology 98: 337-340, 2010.

11. 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.; 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.

12. Griffin, J. H.; Gruber, A.; Fernandez, J. A.: Reevaluation of
total, free, and bound protein S and C4b-binding protein levels in
plasma anticoagulated with citrate or hirudin. Blood 79: 3203-3211,
1992.

13. Hartz, P. A.: Personal Communication. Baltimore, Md. 9/30/2008.

14. Hayashi, T.; Nishioka, J.; Shigekiyo, T.; Saito, S.; Suzuki, K.
: Protein S Tokushima: abnormal molecule with a substitution of glu
for lys-155 in the second epidermal growth factor-like domain of protein
S. Blood 83: 683-690, 1994.

15. Heeb, M. J.; Rosing, J.; Bakker, H. M.; Fernandez, J. A.; Tans,
G.; Griffin, J. H.: Protein S binds to and inhibits factor Xa. Proc.
Nat. Acad. Sci. 91: 2728-2732, 1994.

16. Hoskins, J.; Norman, D. K.; Beckmann, R. J.; Long, G. L.: Cloning
and characterization of human liver cDNA encoding a protein S precursor. Proc.
Nat. Acad. Sci. 84: 349-353, 1987.

17. 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.

18. Long, G. L.; Marshall, A.; Gardner, J. C.; Naylor, S. L.: Genes
for human vitamin K-dependent plasma proteins C and S are located
on chromosomes 2 and 3, respectively. Somat. Cell Molec. Genet. 14:
93-98, 1988.

19. Lundwall, A.; Dackowski, W.; Cohen, E.; Shaffer, M.; Mahr, A.;
Dahlback, B.; Stenflo, J.; Wydro, R.: Isolation and sequence of the
cDNA for human protein S, a regulator of blood coagulation. Proc.
Nat. Acad. Sci. 83: 6716-6720, 1986.

20. Mahasandana, C.; Suvatte, V.; Chuansumrit, A.; Marlar, R. A.;
Manco-Johnson, M. J.; Jacobson, L. J.; Hathaway, W. E.: Homozygous
protein S deficiency in an infant with purpura fulminans. J. Pediat. 117:
750-753, 1990.

21. 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.

22. Naylor, S. L.; Marshall, A.; Solomon, A.; Long, G.: Mapping human
protein C and protein S to chromosomes 2 and 3, respectively. (Abstract) Cytogenet.
Cell Genet. 46: 669 only, 1987.

23. 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.

24. Ploos van Amstel, H. K.; Huisman, M. V.; Reitsma, P. H.; ten Cate,
J.; Bertina, R. M.: Partial protein S gene deletion in a family with
hereditary thrombophilia. Blood 73: 479-483, 1989.

25. Ploos van Amstel, H. K.; Reitsma, P. H.; Bertina, R. M.: The
human protein S locus: identification of the PS-alpha gene as a site
of liver protein S messenger RNA synthesis. Biochem. Biophys. Res.
Commun. 157: 1033-1038, 1988.

26. Ploos van Amstel, J. K.; van der Zanden, A. L.; Bakker, E.; Reitsma,
P. H.; Bertina, R. M.: Two genes homologous with human protein S
cDNA are located on chromosome 3. Thromb. Haemost. 58: 982-987,
1987.

27. Pung-amritt, P.; Poort, S. R.; Vos, H. L.; Bertina, R. M.; Mahasandana,
C.; Tanphaichitr, V. S.; Veerakul, G.; Kankirawatana, S.; Suvatte,
V.: Compound heterozygosity for one novel and one recurrent mutation
in a Thai patient with severe protein S deficiency. Thromb. Haemost. 81:
189-192, 1999.

28. Reitsma, P. H.; Ploos van Amstel, H. K.; Bertina, R. M.: Three
novel mutations in five unrelated subjects with hereditary protein
S deficiency type I. J. Clin. Invest. 93: 486-492, 1994.

29. Saller, F.; Brisset, A. C.; Tchaikovski, S. N.; Azevedo, M.; Chrast,
R.; Fernandez, J. A.; Schapira, M.; Hackeng, T. M.; Griffin, J. H.;
Angelillo-Scherrer, A.: Generation and phenotypic analysis of protein
S-deficient mice. Blood 114: 2307-2314, 2009.

30. Schmidel, D. K.; Tatro, A. V.; Phelps, L. G.; Tomczak, J. A.;
Long, G. I.: Organization of the human protein S genes. Biochemistry 29:
7845-7852, 1990.

31. Schwarz, H. P.; Heeb, M. J.; Lottenberg, R.; Roberts, H.; Griffin,
J. H.: Familial protein S deficiency with a variant protein S molecule
in plasma and platelets. Blood 74: 213-221, 1989.

32. Stanislovitis, P.; Watkins, P. C.; Eddy, R.; Cohen, E. H.; Dackowski,
W. R.; Wydro, R. M.; Shows, T. B.: Regional assignment of the gene
for protein S to the human chromosome region 3p21-3q21. (Abstract) Am.
J. Hum. Genet. 41: A187 only, 1987.

33. Watkins, P. C.; Eddy, R.; Fukushima, Y.; Byers, M. G.; Cohen,
E. H.; Dackowski, W. R.; Wydro, R. M.; Shows, T. B.: The gene for
protein S maps near the centromere of human chromosome 3. Blood 71:
238-241, 1988.

34. Watkins, P. C.; Eddy, R.; Fukushima, Y.; Byers, M. G.; Cohen,
E. H.; Dackowski, W. R.; Wydro, R. M.; Shows, T. B.: Regional assignment
of the gene for protein S (PROS) to the human chromosome region 3p11.1-q11.2.
(Abstract) Cytogenet. Cell Genet. 46: 712 only, 1987.

*FIELD* CN
Cassandra L. Kniffin - updated: 3/1/2012
Patricia A. Hartz - updated: 5/10/2011
Cassandra L. Kniffin - updated: 3/23/2011
Cassandra L. Kniffin - updated: 8/16/2010
Cassandra L. Kniffin - updated: 5/21/2010
Cassandra L. Kniffin - reorganized: 10/9/2008
Cassandra L. Kniffin - updated: 10/8/2008
Victor A. McKusick - updated: 8/24/2004
Paul J. Converse - updated: 12/20/2002
Jane Kelly - updated: 7/16/2001
Victor A. McKusick - updated: 4/26/2000
Jane Kelly - updated: 8/27/1999
Victor A. McKusick - updated: 7/22/1999
Victor A. McKusick - updated: 9/8/1998
Victor A. McKusick - edited: 2/24/1997
Orest Hurko - updated: 6/13/1995

*FIELD* CD
Victor A. McKusick: 6/2/1986

*FIELD* ED
carol: 03/01/2012
ckniffin: 3/1/2012
carol: 3/1/2012
carol: 2/28/2012
mgross: 5/18/2011
terry: 5/10/2011
carol: 4/7/2011
wwang: 4/5/2011
ckniffin: 3/23/2011
joanna: 8/25/2010
wwang: 8/18/2010
ckniffin: 8/16/2010
wwang: 5/24/2010
ckniffin: 5/21/2010
carol: 10/9/2008
ckniffin: 10/8/2008
carol: 10/1/2008
tkritzer: 9/3/2004
terry: 8/24/2004
carol: 3/17/2004
alopez: 1/9/2003
mgross: 12/20/2002
carol: 7/17/2001
carol: 7/16/2001
carol: 12/26/2000
mcapotos: 5/24/2000
terry: 4/26/2000
alopez: 11/18/1999
carol: 8/27/1999
jlewis: 8/24/1999
jlewis: 8/17/1999
jlewis: 8/2/1999
terry: 7/22/1999
dkim: 12/16/1998
carol: 11/16/1998
dkim: 9/14/1998
terry: 9/8/1998
terry: 7/24/1998
jenny: 2/25/1997
jenny: 2/24/1997
mark: 6/13/1995
mimadm: 2/25/1995
carol: 11/15/1994
davew: 8/5/1994
jason: 7/15/1994
carol: 12/20/1993

MIM 612336
*RECORD*
*FIELD* NO
612336
*FIELD* TI
#612336 THROMBOPHILIA DUE TO PROTEIN S DEFICIENCY, AUTOSOMAL DOMINANT; THPH5
*FIELD* TX
read moreA number sign (#) is used with this entry because thrombophilia due to
protein S deficiency (THPH5) is caused by heterozygous mutation in the
gene encoding protein S (PROS1; 176880) on chromosome 3q11.

DESCRIPTION

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.

CLINICAL FEATURES

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).

OTHER FEATURES

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.

DIAGNOSIS

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.

MOLECULAR GENETICS

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.

*FIELD* SA
Phillips et al. (1992); Sas et al. (1985)
*FIELD* RF
1. 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.

2. Bertina, R. M.: Nomenclature proposal for protein S deficiency.
XXXVI Annual meeting of the Scientific and Standardization Committee
of the ISTH Barcelona, Spain , 1990.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. Golub, B. M.; Sibony, P. A.; Coller, B. S.: Protein S deficiency
associated with central retinal artery occlusion. Arch. Ophthal. 108:
918 only, 1990.

12. 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.

13. 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.

14. 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.

15. 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.

16. Malnick, S. D. H.; Sthoeger, Z. M.: Autoimmune protein S deficiency. New
Eng. J. Med. 329: 1898 only, 1993.

17. Mannucci, P. M.; Valsecchi, C.; Krachmalnicoff, A.; Faioni, E.
M.; Tripodi, A.: Familial dysfunction of protein S. Thromb. Haemost. 62:
763-766, 1989.

18. 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.

19. 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.

20. 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.

21. 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.

22. 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.

23. 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.

24. 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.

*FIELD* CS
INHERITANCE:
Autosomal dominant

CARDIOVASCULAR:
[Vascular];
Venous thrombosis, recurrent;
Mesenteric thrombosis;
Cerebral venous thrombosis;
Arterial thrombosis;
Superficial thrombophlebitis

RESPIRATORY:
[Lung];
Pulmonary embolism

SKIN, NAILS, HAIR:
[Skin];
Warfarin-induced skin necrosis

LABORATORY ABNORMALITIES:
Absent/reduced protein S and normal total proteins in heterozygote

MISCELLANEOUS:
Protein S deficiency is found in 2-3% of patients with thromboembolism;
Acquired protein S deficiency seen in pregnancy, oral contraceptive
use, warfarin use, liver disease, DIC, and diabetes

MOLECULAR BASIS:
Caused by mutation in the protein S gene (PSA, 176880.0002)

*FIELD* CN
Kelly A. Przylepa - revised: 8/22/2000

*FIELD* ED
joanna: 04/01/2012
ckniffin: 3/1/2012
joanna: 11/5/2008
ckniffin: 10/8/2008
joanna: 9/4/2001
kayiaros: 8/22/2000

*FIELD* CN
Cassandra L. Kniffin - updated: 3/23/2011
Cassandra L. Kniffin - updated: 5/21/2010
Cassandra L. Kniffin - updated: 10/8/2008

*FIELD* CD
Cassandra L. Kniffin: 10/1/2008

*FIELD* ED
carol: 03/01/2012
ckniffin: 3/1/2012
carol: 3/1/2012
carol: 2/28/2012
ckniffin: 2/23/2012
terry: 2/3/2012
wwang: 4/5/2011
ckniffin: 3/23/2011
wwang: 5/24/2010
ckniffin: 5/21/2010
carol: 10/9/2008
ckniffin: 10/8/2008
carol: 10/1/2008

MIM 614514
*RECORD*
*FIELD* NO
614514
*FIELD* TI
#614514 THROMBOPHILIA DUE TO PROTEIN S DEFICIENCY, AUTOSOMAL RECESSIVE; THPH6
*FIELD* TX
read moreA number sign (#) is used with this entry because autosomal recessive
thrombophilia due to protein S deficiency (THPH6) is caused by
homozygous or compound heterozygous mutation in the gene encoding
protein S (PROS1; 176880) on chromosome 3q11.

DESCRIPTION

Autosomal recessive thrombophilia due to protein S deficiency is a very
rare and severe hematologic disorder resulting in thrombosis and
secondary hemorrhage usually beginning in early infancy. Some affected
individuals develop neonatal purpura fulminans, multifocal thrombosis,
or intracranial hemorrhage (Pung-amritt et al., 1999; Fischer et al.,
2010), whereas others have recurrent thromboses later in childhood (Comp
et al., 1984).

See also autosomal dominant thrombophilia due to protein S deficiency
(THPH5; 612336), a less severe disorder caused by heterozygous mutation
in the PROS1 gene.

CLINICAL FEATURES

Comp et al. (1984) reported 2 brothers with thrombophilia associated
with homozygous protein S deficiency. Both had recurrent venous
thromboses beginning in their teenage years. Laboratory studies showed
no detectable protein S activity in either brother, whereas both
asymptomatic parents had activities that were 15% and 30% of normal.
Free protein S in the patients was essentially absent, although there
was detectable protein S complexed to C4BPA (120830).

Kamiya et al. (1986) observed affected persons in 3 generations of a
Japanese kindred, including several persons of consanguineous parentage
who had severe deficiency of protein S and were presumably homozygous
for the defect.

Autosomal recessive protein C deficiency (612304) has been described as
the basis of neonatal purpura fulminans. Mahasandana et al. (1990)
described neonatal purpura fulminans in a female Thai infant with
homozygous protein S deficiency. Although there was no family history of
thrombotic tendency and the parents were not known to be related, there
were only trace amounts of free protein S in blood samples from the
parents in initial studies. Pung-amritt et al. (1999) provided follow-up
on the patient reported by Mahasandana et al. (1990). She had presented
at age 10 days with neonatal purpura fulminans and later developed
disseminated intravascular coagulation, which responded to
cryoprecipitate transfusion. She was found to have endophthalmitis and
was blind, suggesting retinal vessel thrombosis in utero. Protein S was
almost undetectable in the patient's plasma.

Bosson et al. (1995) described multiple thromboembolic venous occlusive
complications in an 8-day-old infant who developed microthrombosis of
the skin, superficial venous thrombosis, and deep venous thrombosis of
the leg with a pulmonary embolism.

Mintz-Hittner et al. (1999) described vitreoretinal findings similar to
severe retinopathy of prematurity (ROP) in 2 sibs with complete protein
S deficiency born at 40 and 34 weeks' gestation, respectively. Both
parents had heterozygous protein S deficiency. Normal vasculogenesis was
interrupted in both children, and only 1 of the 4 eyes retained
functional vision. A normal-appearing posterior retina, normal scotopic
and photopic flash electroretinograms (ERGs), and a normal flash visual
evoked response were documented from the left eye of the son at 62
weeks' adjusted age. The other 3 eyes had inoperable retinal detachments
and no functional vision. Mintz-Hittner et al. (1999) concluded that
patients with homozygous or compound heterozygous protein S deficiency
might present as infants with severe ROP.

Fischer et al. (2010) reported an Albanian infant who presented on the
fourth day of life with seizures and hemorrhagic shock associated with a
massive intracranial bleed and laboratory evidence of disseminated
intravascular coagulation. After stabilization, laboratory studies
showed thrombophilia due to severe protein S deficiency (less than 10%
activity). The infant later developed acute arterial thrombosis of the
aorta and died on the eighth day of life. Postmortem examination showed
diffuse thromboses of intracerebral capillaries, suggesting that the
underlying prothrombotic condition resulted in hemorrhage.

MOLECULAR GENETICS

In a Thai infant with autosomal recessive thrombophilia due to protein S
deficiency (Mahasandana et al., 1990), Pung-amritt et al. (1999)
identified compound heterozygosity for 2 mutations in the PROS1 gene
(176880.0010 and 176880.0011). Each parent, who was found by ELISA
studies to have about 50% of protein S free antigen, was heterozygous
for 1 of the mutations.

In an infant, born of Albanian parents, with autosomal recessive
thrombophilia due to protein S deficiency, Fischer et al. (2010)
identified a homozygous mutation in the PROS1 gene (176880.0012). Each
parent was heterozygous for the mutation and showed about 50% protein S
activity.

*FIELD* RF
1. Bosson, J. L.; Francois, P.; Pernod, G.; Carpentier, P.: Maladie
thrombo-embolique veineuse chez l'enfant liee a un deficit transitoire
en proteine S au decours d'une varicelle. (Letter) Presse Med. 24:
415 only, 1995.

2. Comp, P. C.; Nixon, R. R.; Cooper, M. R.; Esmon, C. T.: Familial
protein S deficiency is associated with recurrent thrombosis. J.
Clin. Invest. 74: 2082-2088, 1984.

3. Fischer, D.; Porto, L.; Stoll, H.; Geisen, C.; Schloesser, R. L.
: Intracerebral mass bleeding in a term neonate: manifestation of
hereditary protein S deficiency with a new mutation in the PROS1 gene. Neonatology 98:
337-340, 2010.

4. Kamiya, T.; Sugihara, T.; Ogata, K.; Saito, H.; Suzuki, K.; Nishioka,
J.; Hashimoto, S.; Yamagata, K.: Inherited deficiency of protein
S in a Japanese family with recurrent venous thrombosis: a study of
three generations. Blood 67: 406-410, 1986.

5. Mahasandana, C.; Suvatte, V.; Chuansumrit, A.; Marlar, R. A.; Manco-Johnson,
M. J.; Jacobson, L. J.; Hathaway, W. E.: Homozygous protein S deficiency
in an infant with purpura fulminans. J. Pediat. 117: 750-753, 1990.

6. Mintz-Hittner, H. A.; Miyashiro, M. J.; Knight-Nanan, D. M.; O'Malley,
R. E.; Marlar, R. A.: Vitreoretinal findings similar to retinopathy
of prematurity in infants with compound heterozygous protein S deficiency. Ophthalmology 106:
1525-1530, 1999.

7. Pung-amritt, P.; Poort, S. R.; Vos, H. L.; Bertina, R. M.; Mahasandana,
C.; Tanphaichitr, V. S.; Veerakul, G.; Kankirawatana, S.; Suvatte,
V.: Compound heterozygosity for one novel and one recurrent mutation
in a Thai patient with severe protein S deficiency. Thromb. Haemost. 81:
189-192, 1999.

*FIELD* CS
INHERITANCE:
Autosomal recessive

HEAD AND NECK:
[Eyes];
Retinal thrombosis;
Impaired retinal vasculogenesis;
Blindness

CARDIOVASCULAR:
[Vascular];
Venous thrombosis, recurrent;
Mesenteric thrombosis;
Cerebral venous thrombosis;
Intracerebral hemorrhage (secondary);
Arterial thrombosis;
Superficial thrombophlebitis

RESPIRATORY:
[Lung];
Pulmonary embolism

SKIN, NAILS, HAIR:
[Skin];
Neonatal purpura fulminans;
Skin necrosis

LABORATORY ABNORMALITIES:
Absent/reduced free proteins and absent total protein S;
Disseminated intravascular coagulation

MISCELLANEOUS:
Onset in infancy or childhood;
Increased abortuses of homozygous or compound heterozygous fetuses;
Secondary hemorrhage

MOLECULAR BASIS:
Caused by mutation in the protein S gene (PROS1, 176880.0010)

*FIELD* CD
Cassandra L. Kniffin: 3/1/2012

*FIELD* ED
joanna: 04/01/2012
ckniffin: 3/1/2012

*FIELD* CD
Cassandra L. Kniffin: 3/1/2012

*FIELD* ED
terry: 03/06/2012
carol: 3/1/2012
ckniffin: 3/1/2012