Full text data of KLKB1
KLKB1
(KLK3)
[Confidence: low (only semi-automatic identification from reviews)]
Plasma kallikrein; 3.4.21.34 (Fletcher factor; Kininogenin; Plasma prekallikrein; Plasma kallikrein heavy chain; Plasma kallikrein light chain; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
Plasma kallikrein; 3.4.21.34 (Fletcher factor; Kininogenin; Plasma prekallikrein; Plasma kallikrein heavy chain; Plasma kallikrein light chain; Flags: Precursor)
Note: presumably soluble (membrane word is not in UniProt keywords or features)
UniProt
P03952
ID KLKB1_HUMAN Reviewed; 638 AA.
AC P03952; A6NH96; B2R8H9; Q17RE8; Q17RE9; Q4W5C3;
DT 23-OCT-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-OCT-1986, sequence version 1.
DT 22-JAN-2014, entry version 161.
DE RecName: Full=Plasma kallikrein;
DE EC=3.4.21.34;
DE AltName: Full=Fletcher factor;
DE AltName: Full=Kininogenin;
DE AltName: Full=Plasma prekallikrein;
DE Contains:
DE RecName: Full=Plasma kallikrein heavy chain;
DE Contains:
DE RecName: Full=Plasma kallikrein light chain;
DE Flags: Precursor;
GN Name=KLKB1; Synonyms=KLK3;
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=3521732; DOI=10.1021/bi00357a017;
RA Chung D.W., Fujikawa K., McMullen B.A., Davie E.W.;
RT "Human plasma prekallikrein, a zymogen to a serine protease that
RT contains four tandem repeats.";
RL Biochemistry 25:2410-2417(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS SER-143; GLN-202 AND
RP PRO-208.
RX PubMed=11031105; DOI=10.1006/geno.2000.6330;
RA Yu H., Anderson P.J., Freedman B.I., Rich S.S., Bowden D.W.;
RT "Genomic structure of the human plasma prekallikrein gene,
RT identification of allelic variants, and analysis in end-stage renal
RT disease.";
RL Genomics 69:225-234(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
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 [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS SER-143; THR-178;
RP GLN-202; CYS-269; VAL-311; ALA-358; ALA-381; PRO-442 AND GLN-560.
RG SeattleSNPs variation discovery resource;
RL Submitted (DEC-2002) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [6]
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT GLN-560.
RC TISSUE=Colon;
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 [8]
RP PARTIAL PROTEIN SEQUENCE, AND DISULFIDE BONDS.
RX PubMed=1998666; DOI=10.1021/bi00222a007;
RA McMullen B.A., Fujikawa K., Davie E.W.;
RT "Location of the disulfide bonds in human plasma prekallikrein: the
RT presence of four novel apple domains in the amino-terminal portion of
RT the molecule.";
RL Biochemistry 30:2050-2056(1991).
RN [9]
RP ENZYME REGULATION, AND HETERODIMER WITH SERPINA5.
RX PubMed=2844223; DOI=10.1021/bi00412a005;
RA Meijers J.C., Kanters D.H., Vlooswijk R.A., van Erp H.E., Hessing M.,
RA Bouma B.N.;
RT "Inactivation of human plasma kallikrein and factor XIa by protein C
RT inhibitor.";
RL Biochemistry 27:4231-4237(1988).
RN [10]
RP GLYCOSYLATION AT ASN-453.
RX PubMed=12754519; DOI=10.1038/nbt827;
RA Zhang H., Li X.-J., Martin D.B., Aebersold R.;
RT "Identification and quantification of N-linked glycoproteins using
RT hydrazide chemistry, stable isotope labeling and mass spectrometry.";
RL Nat. Biotechnol. 21:660-666(2003).
RN [11]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-127; ASN-308; ASN-396;
RP ASN-453 AND ASN-494, AND MASS 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 GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-308; ASN-396; ASN-453 AND
RP ASN-494, AND MASS SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [13]
RP VARIANT PKK DEFICIENCY TYR-548.
RX PubMed=14652634; DOI=10.1267/THRO03061040;
RA Lombardi A.M., Sartori M.T., Cabrio L., Fadin M., Zanon E.,
RA Girolami A.;
RT "Severe prekallikrein (Fletcher factor) deficiency due to a compound
RT heterozygosis (383Trp stop codon and Cys529Tyr).";
RL Thromb. Haemost. 90:1040-1045(2003).
RN [14]
RP VARIANTS PKK DEFICIENCY ARG-123 AND SER-143.
RX PubMed=17598838; DOI=10.1111/j.1600-0609.2007.00871.x;
RA Katsuda I., Maruyama F., Ezaki K., Sawamura T., Ichihara Y.;
RT "A new type of plasma prekallikrein deficiency associated with
RT homozygosity for Gly104Arg and Asn124Ser in apple domain 2 of the
RT heavy-chain region.";
RL Eur. J. Haematol. 79:59-68(2007).
CC -!- FUNCTION: The enzyme cleaves Lys-Arg and Arg-Ser bonds. It
CC activates, in a reciprocal reaction, factor XII after its binding
CC to a negatively charged surface. It also releases bradykinin from
CC HMW kininogen and may also play a role in the renin-angiotensin
CC system by converting prorenin into renin.
CC -!- CATALYTIC ACTIVITY: Cleaves selectively Arg-|-Xaa and Lys-|-Xaa
CC bonds, including Lys-|-Arg and Arg-|-Ser bonds in (human)
CC kininogen to release bradykinin.
CC -!- ENZYME REGULATION: Inhibited by SERPINA5.
CC -!- SUBUNIT: Forms a heterodimer with SERPINA5. The zymogen is
CC activated by factor XIIa, which cleaves the molecule into a light
CC chain, which contains the active site, and a heavy chain, which
CC associates with HMW kininogen. These chains are linked by one or
CC more disulfide bonds.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- DISEASE: Prekallikrein deficiency (PKK deficiency) [MIM:612423]:
CC This disorder is a blood coagulation defect. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the peptidase S1 family. Plasma kallikrein
CC subfamily.
CC -!- SIMILARITY: Contains 4 apple domains.
CC -!- SIMILARITY: Contains 1 peptidase S1 domain.
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/klkb1/";
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DR EMBL; M13143; AAA60153.1; -; mRNA.
DR EMBL; AF232742; AAF79940.1; -; Genomic_DNA.
DR EMBL; AF232734; AAF79940.1; JOINED; Genomic_DNA.
DR EMBL; AF232735; AAF79940.1; JOINED; Genomic_DNA.
DR EMBL; AF232736; AAF79940.1; JOINED; Genomic_DNA.
DR EMBL; AF232737; AAF79940.1; JOINED; Genomic_DNA.
DR EMBL; AF232738; AAF79940.1; JOINED; Genomic_DNA.
DR EMBL; AF232739; AAF79940.1; JOINED; Genomic_DNA.
DR EMBL; AF232740; AAF79940.1; JOINED; Genomic_DNA.
DR EMBL; AF232741; AAF79940.1; JOINED; Genomic_DNA.
DR EMBL; AK313378; BAG36176.1; -; mRNA.
DR EMBL; AY190920; AAN84794.1; -; Genomic_DNA.
DR EMBL; AC110771; AAY40900.1; -; Genomic_DNA.
DR EMBL; CH471056; EAX04623.1; -; Genomic_DNA.
DR EMBL; BC117349; AAI17350.1; -; mRNA.
DR EMBL; BC117351; AAI17352.1; -; mRNA.
DR PIR; A00921; KQHUP.
DR RefSeq; NP_000883.2; NM_000892.3.
DR UniGene; Hs.237642; -.
DR PDB; 2ANW; X-ray; 1.85 A; A=391-631.
DR PDB; 2ANY; X-ray; 1.40 A; A=391-631.
DR PDBsum; 2ANW; -.
DR PDBsum; 2ANY; -.
DR ProteinModelPortal; P03952; -.
DR SMR; P03952; 21-628.
DR STRING; 9606.ENSP00000264690; -.
DR BindingDB; P03952; -.
DR ChEMBL; CHEMBL2111419; -.
DR MEROPS; S01.212; -.
DR PhosphoSite; P03952; -.
DR DMDM; 125184; -.
DR PaxDb; P03952; -.
DR PRIDE; P03952; -.
DR DNASU; 3818; -.
DR Ensembl; ENST00000264690; ENSP00000264690; ENSG00000164344.
DR GeneID; 3818; -.
DR KEGG; hsa:3818; -.
DR UCSC; uc011clc.2; human.
DR CTD; 3818; -.
DR GeneCards; GC04P187130; -.
DR HGNC; HGNC:6371; KLKB1.
DR HPA; HPA005634; -.
DR MIM; 229000; gene.
DR MIM; 612423; phenotype.
DR neXtProt; NX_P03952; -.
DR Orphanet; 749; Congenital prekallikrein deficiency.
DR PharmGKB; PA30160; -.
DR eggNOG; COG5640; -.
DR HOGENOM; HOG000112467; -.
DR HOVERGEN; HBG000399; -.
DR InParanoid; P03952; -.
DR KO; K01324; -.
DR BRENDA; 3.4.21.34; 2681.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR Reactome; REACT_604; Hemostasis.
DR EvolutionaryTrace; P03952; -.
DR GeneWiki; KLKB1; -.
DR GenomeRNAi; 3818; -.
DR NextBio; 15011; -.
DR PMAP-CutDB; Q4W5C3; -.
DR PRO; PR:P03952; -.
DR ArrayExpress; P03952; -.
DR Bgee; P03952; -.
DR CleanEx; HS_KLK3; -.
DR CleanEx; HS_KLKB1; -.
DR Genevestigator; P03952; -.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0004252; F:serine-type endopeptidase activity; TAS:ProtInc.
DR GO; GO:0007597; P:blood coagulation, intrinsic pathway; TAS:Reactome.
DR GO; GO:0022617; P:extracellular matrix disassembly; TAS:Reactome.
DR GO; GO:0002542; P:Factor XII activation; TAS:BHF-UCL.
DR GO; GO:0042730; P:fibrinolysis; IEA:UniProtKB-KW.
DR GO; GO:0031639; P:plasminogen activation; IDA:BHF-UCL.
DR GO; GO:0051919; P:positive regulation of fibrinolysis; IDA:BHF-UCL.
DR GO; GO:0006508; P:proteolysis; TAS:ProtInc.
DR InterPro; IPR000177; Apple.
DR InterPro; IPR003014; PAN-1_domain.
DR InterPro; IPR003609; Pan_app.
DR InterPro; IPR001254; Peptidase_S1.
DR InterPro; IPR018114; Peptidase_S1_AS.
DR InterPro; IPR001314; Peptidase_S1A.
DR InterPro; IPR009003; Trypsin-like_Pept_dom.
DR Pfam; PF00024; PAN_1; 4.
DR Pfam; PF00089; Trypsin; 1.
DR PRINTS; PR00005; APPLEDOMAIN.
DR PRINTS; PR00722; CHYMOTRYPSIN.
DR SMART; SM00223; APPLE; 4.
DR SMART; SM00020; Tryp_SPc; 1.
DR SUPFAM; SSF50494; SSF50494; 1.
DR PROSITE; PS00495; APPLE; 4.
DR PROSITE; PS50948; PAN; 4.
DR PROSITE; PS50240; TRYPSIN_DOM; 1.
DR PROSITE; PS00134; TRYPSIN_HIS; 1.
DR PROSITE; PS00135; TRYPSIN_SER; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Blood coagulation; Complete proteome;
KW Direct protein sequencing; Disease mutation; Disulfide bond;
KW Fibrinolysis; Glycoprotein; Hemostasis; Hydrolase;
KW Inflammatory response; Polymorphism; Protease; Reference proteome;
KW Repeat; Secreted; Serine protease; Signal; Zymogen.
FT SIGNAL 1 19
FT CHAIN 20 390 Plasma kallikrein heavy chain.
FT /FTId=PRO_0000028021.
FT CHAIN 391 638 Plasma kallikrein light chain.
FT /FTId=PRO_0000028022.
FT DOMAIN 21 104 Apple 1.
FT DOMAIN 111 194 Apple 2.
FT DOMAIN 201 284 Apple 3.
FT DOMAIN 292 375 Apple 4.
FT DOMAIN 391 626 Peptidase S1.
FT ACT_SITE 434 434 Charge relay system.
FT ACT_SITE 483 483 Charge relay system.
FT ACT_SITE 578 578 Charge relay system.
FT CARBOHYD 127 127 N-linked (GlcNAc...).
FT CARBOHYD 308 308 N-linked (GlcNAc...).
FT CARBOHYD 396 396 N-linked (GlcNAc...).
FT CARBOHYD 453 453 N-linked (GlcNAc...).
FT CARBOHYD 494 494 N-linked (GlcNAc...).
FT DISULFID 21 104
FT DISULFID 47 77
FT DISULFID 51 57
FT DISULFID 111 194
FT DISULFID 137 166
FT DISULFID 141 147
FT DISULFID 201 284
FT DISULFID 227 256
FT DISULFID 231 237
FT DISULFID 292 375
FT DISULFID 318 347
FT DISULFID 322 328
FT DISULFID 340 345
FT DISULFID 383 503
FT DISULFID 419 435
FT DISULFID 517 584
FT DISULFID 548 563
FT DISULFID 574 602
FT VARIANT 123 123 G -> R (in PKK deficiency; reduces the
FT binding activity of Apple domain 2 to HMW
FT kininogen).
FT /FTId=VAR_054907.
FT VARIANT 143 143 N -> S (in PKK deficiency; reduces the
FT binding activity of Apple domain 2 to HMW
FT kininogen; dbSNP:rs3733402).
FT /FTId=VAR_013598.
FT VARIANT 178 178 A -> T (in dbSNP:rs4253257).
FT /FTId=VAR_016280.
FT VARIANT 202 202 H -> Q (in dbSNP:rs4253373).
FT /FTId=VAR_013599.
FT VARIANT 208 208 H -> P.
FT /FTId=VAR_013600.
FT VARIANT 210 210 A -> E (in dbSNP:rs2278542).
FT /FTId=VAR_020180.
FT VARIANT 269 269 S -> C (in dbSNP:rs4253376).
FT /FTId=VAR_016281.
FT VARIANT 311 311 F -> V (in dbSNP:rs4253377).
FT /FTId=VAR_016282.
FT VARIANT 358 358 T -> A (in dbSNP:rs4253379).
FT /FTId=VAR_016283.
FT VARIANT 381 381 S -> A (in dbSNP:rs4253301).
FT /FTId=VAR_016284.
FT VARIANT 442 442 Q -> P (in dbSNP:rs4253316).
FT /FTId=VAR_016285.
FT VARIANT 548 548 C -> Y (in PKK deficiency).
FT /FTId=VAR_054908.
FT VARIANT 560 560 R -> Q (in dbSNP:rs4253325).
FT /FTId=VAR_016286.
FT STRAND 405 425
FT STRAND 428 431
FT HELIX 433 436
FT HELIX 442 444
FT STRAND 445 448
FT HELIX 454 456
FT STRAND 466 471
FT STRAND 479 482
FT STRAND 485 491
FT HELIX 507 511
FT STRAND 515 523
FT STRAND 525 528
FT STRAND 536 543
FT HELIX 545 549
FT STRAND 561 564
FT STRAND 581 586
FT STRAND 589 598
FT STRAND 600 603
FT STRAND 609 613
FT HELIX 614 617
FT HELIX 618 625
SQ SEQUENCE 638 AA; 71370 MW; E62F9C1053838FB4 CRC64;
MILFKQATYF ISLFATVSCG CLTQLYENAF FRGGDVASMY TPNAQYCQMR CTFHPRCLLF
SFLPASSIND MEKRFGCFLK DSVTGTLPKV HRTGAVSGHS LKQCGHQISA CHRDIYKGVD
MRGVNFNVSK VSSVEECQKR CTNNIRCQFF SYATQTFHKA EYRNNCLLKY SPGGTPTAIK
VLSNVESGFS LKPCALSEIG CHMNIFQHLA FSDVDVARVL TPDAFVCRTI CTYHPNCLFF
TFYTNVWKIE SQRNVCLLKT SESGTPSSST PQENTISGYS LLTCKRTLPE PCHSKIYPGV
DFGGEELNVT FVKGVNVCQE TCTKMIRCQF FTYSLLPEDC KEEKCKCFLR LSMDGSPTRI
AYGTQGSSGY SLRLCNTGDN SVCTTKTSTR IVGGTNSSWG EWPWQVSLQV KLTAQRHLCG
GSLIGHQWVL TAAHCFDGLP LQDVWRIYSG ILNLSDITKD TPFSQIKEII IHQNYKVSEG
NHDIALIKLQ APLNYTEFQK PICLPSKGDT STIYTNCWVT GWGFSKEKGE IQNILQKVNI
PLVTNEECQK RYQDYKITQR MVCAGYKEGG KDACKGDSGG PLVCKHNGMW RLVGITSWGE
GCARREQPGV YTKVAEYMDW ILEKTQSSDG KAQMQSPA
//
ID KLKB1_HUMAN Reviewed; 638 AA.
AC P03952; A6NH96; B2R8H9; Q17RE8; Q17RE9; Q4W5C3;
DT 23-OCT-1986, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-OCT-1986, sequence version 1.
DT 22-JAN-2014, entry version 161.
DE RecName: Full=Plasma kallikrein;
DE EC=3.4.21.34;
DE AltName: Full=Fletcher factor;
DE AltName: Full=Kininogenin;
DE AltName: Full=Plasma prekallikrein;
DE Contains:
DE RecName: Full=Plasma kallikrein heavy chain;
DE Contains:
DE RecName: Full=Plasma kallikrein light chain;
DE Flags: Precursor;
GN Name=KLKB1; Synonyms=KLK3;
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=3521732; DOI=10.1021/bi00357a017;
RA Chung D.W., Fujikawa K., McMullen B.A., Davie E.W.;
RT "Human plasma prekallikrein, a zymogen to a serine protease that
RT contains four tandem repeats.";
RL Biochemistry 25:2410-2417(1986).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS SER-143; GLN-202 AND
RP PRO-208.
RX PubMed=11031105; DOI=10.1006/geno.2000.6330;
RA Yu H., Anderson P.J., Freedman B.I., Rich S.S., Bowden D.W.;
RT "Genomic structure of the human plasma prekallikrein gene,
RT identification of allelic variants, and analysis in end-stage renal
RT disease.";
RL Genomics 69:225-234(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Liver;
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 [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS SER-143; THR-178;
RP GLN-202; CYS-269; VAL-311; ALA-358; ALA-381; PRO-442 AND GLN-560.
RG SeattleSNPs variation discovery resource;
RL Submitted (DEC-2002) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [6]
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT GLN-560.
RC TISSUE=Colon;
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 [8]
RP PARTIAL PROTEIN SEQUENCE, AND DISULFIDE BONDS.
RX PubMed=1998666; DOI=10.1021/bi00222a007;
RA McMullen B.A., Fujikawa K., Davie E.W.;
RT "Location of the disulfide bonds in human plasma prekallikrein: the
RT presence of four novel apple domains in the amino-terminal portion of
RT the molecule.";
RL Biochemistry 30:2050-2056(1991).
RN [9]
RP ENZYME REGULATION, AND HETERODIMER WITH SERPINA5.
RX PubMed=2844223; DOI=10.1021/bi00412a005;
RA Meijers J.C., Kanters D.H., Vlooswijk R.A., van Erp H.E., Hessing M.,
RA Bouma B.N.;
RT "Inactivation of human plasma kallikrein and factor XIa by protein C
RT inhibitor.";
RL Biochemistry 27:4231-4237(1988).
RN [10]
RP GLYCOSYLATION AT ASN-453.
RX PubMed=12754519; DOI=10.1038/nbt827;
RA Zhang H., Li X.-J., Martin D.B., Aebersold R.;
RT "Identification and quantification of N-linked glycoproteins using
RT hydrazide chemistry, stable isotope labeling and mass spectrometry.";
RL Nat. Biotechnol. 21:660-666(2003).
RN [11]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-127; ASN-308; ASN-396;
RP ASN-453 AND ASN-494, AND MASS 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 GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-308; ASN-396; ASN-453 AND
RP ASN-494, AND MASS SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [13]
RP VARIANT PKK DEFICIENCY TYR-548.
RX PubMed=14652634; DOI=10.1267/THRO03061040;
RA Lombardi A.M., Sartori M.T., Cabrio L., Fadin M., Zanon E.,
RA Girolami A.;
RT "Severe prekallikrein (Fletcher factor) deficiency due to a compound
RT heterozygosis (383Trp stop codon and Cys529Tyr).";
RL Thromb. Haemost. 90:1040-1045(2003).
RN [14]
RP VARIANTS PKK DEFICIENCY ARG-123 AND SER-143.
RX PubMed=17598838; DOI=10.1111/j.1600-0609.2007.00871.x;
RA Katsuda I., Maruyama F., Ezaki K., Sawamura T., Ichihara Y.;
RT "A new type of plasma prekallikrein deficiency associated with
RT homozygosity for Gly104Arg and Asn124Ser in apple domain 2 of the
RT heavy-chain region.";
RL Eur. J. Haematol. 79:59-68(2007).
CC -!- FUNCTION: The enzyme cleaves Lys-Arg and Arg-Ser bonds. It
CC activates, in a reciprocal reaction, factor XII after its binding
CC to a negatively charged surface. It also releases bradykinin from
CC HMW kininogen and may also play a role in the renin-angiotensin
CC system by converting prorenin into renin.
CC -!- CATALYTIC ACTIVITY: Cleaves selectively Arg-|-Xaa and Lys-|-Xaa
CC bonds, including Lys-|-Arg and Arg-|-Ser bonds in (human)
CC kininogen to release bradykinin.
CC -!- ENZYME REGULATION: Inhibited by SERPINA5.
CC -!- SUBUNIT: Forms a heterodimer with SERPINA5. The zymogen is
CC activated by factor XIIa, which cleaves the molecule into a light
CC chain, which contains the active site, and a heavy chain, which
CC associates with HMW kininogen. These chains are linked by one or
CC more disulfide bonds.
CC -!- SUBCELLULAR LOCATION: Secreted.
CC -!- DISEASE: Prekallikrein deficiency (PKK deficiency) [MIM:612423]:
CC This disorder is a blood coagulation defect. Note=The disease is
CC caused by mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the peptidase S1 family. Plasma kallikrein
CC subfamily.
CC -!- SIMILARITY: Contains 4 apple domains.
CC -!- SIMILARITY: Contains 1 peptidase S1 domain.
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/klkb1/";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
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DR EMBL; M13143; AAA60153.1; -; mRNA.
DR EMBL; AF232742; AAF79940.1; -; Genomic_DNA.
DR EMBL; AF232734; AAF79940.1; JOINED; Genomic_DNA.
DR EMBL; AF232735; AAF79940.1; JOINED; Genomic_DNA.
DR EMBL; AF232736; AAF79940.1; JOINED; Genomic_DNA.
DR EMBL; AF232737; AAF79940.1; JOINED; Genomic_DNA.
DR EMBL; AF232738; AAF79940.1; JOINED; Genomic_DNA.
DR EMBL; AF232739; AAF79940.1; JOINED; Genomic_DNA.
DR EMBL; AF232740; AAF79940.1; JOINED; Genomic_DNA.
DR EMBL; AF232741; AAF79940.1; JOINED; Genomic_DNA.
DR EMBL; AK313378; BAG36176.1; -; mRNA.
DR EMBL; AY190920; AAN84794.1; -; Genomic_DNA.
DR EMBL; AC110771; AAY40900.1; -; Genomic_DNA.
DR EMBL; CH471056; EAX04623.1; -; Genomic_DNA.
DR EMBL; BC117349; AAI17350.1; -; mRNA.
DR EMBL; BC117351; AAI17352.1; -; mRNA.
DR PIR; A00921; KQHUP.
DR RefSeq; NP_000883.2; NM_000892.3.
DR UniGene; Hs.237642; -.
DR PDB; 2ANW; X-ray; 1.85 A; A=391-631.
DR PDB; 2ANY; X-ray; 1.40 A; A=391-631.
DR PDBsum; 2ANW; -.
DR PDBsum; 2ANY; -.
DR ProteinModelPortal; P03952; -.
DR SMR; P03952; 21-628.
DR STRING; 9606.ENSP00000264690; -.
DR BindingDB; P03952; -.
DR ChEMBL; CHEMBL2111419; -.
DR MEROPS; S01.212; -.
DR PhosphoSite; P03952; -.
DR DMDM; 125184; -.
DR PaxDb; P03952; -.
DR PRIDE; P03952; -.
DR DNASU; 3818; -.
DR Ensembl; ENST00000264690; ENSP00000264690; ENSG00000164344.
DR GeneID; 3818; -.
DR KEGG; hsa:3818; -.
DR UCSC; uc011clc.2; human.
DR CTD; 3818; -.
DR GeneCards; GC04P187130; -.
DR HGNC; HGNC:6371; KLKB1.
DR HPA; HPA005634; -.
DR MIM; 229000; gene.
DR MIM; 612423; phenotype.
DR neXtProt; NX_P03952; -.
DR Orphanet; 749; Congenital prekallikrein deficiency.
DR PharmGKB; PA30160; -.
DR eggNOG; COG5640; -.
DR HOGENOM; HOG000112467; -.
DR HOVERGEN; HBG000399; -.
DR InParanoid; P03952; -.
DR KO; K01324; -.
DR BRENDA; 3.4.21.34; 2681.
DR Reactome; REACT_118779; Extracellular matrix organization.
DR Reactome; REACT_604; Hemostasis.
DR EvolutionaryTrace; P03952; -.
DR GeneWiki; KLKB1; -.
DR GenomeRNAi; 3818; -.
DR NextBio; 15011; -.
DR PMAP-CutDB; Q4W5C3; -.
DR PRO; PR:P03952; -.
DR ArrayExpress; P03952; -.
DR Bgee; P03952; -.
DR CleanEx; HS_KLK3; -.
DR CleanEx; HS_KLKB1; -.
DR Genevestigator; P03952; -.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0004252; F:serine-type endopeptidase activity; TAS:ProtInc.
DR GO; GO:0007597; P:blood coagulation, intrinsic pathway; TAS:Reactome.
DR GO; GO:0022617; P:extracellular matrix disassembly; TAS:Reactome.
DR GO; GO:0002542; P:Factor XII activation; TAS:BHF-UCL.
DR GO; GO:0042730; P:fibrinolysis; IEA:UniProtKB-KW.
DR GO; GO:0031639; P:plasminogen activation; IDA:BHF-UCL.
DR GO; GO:0051919; P:positive regulation of fibrinolysis; IDA:BHF-UCL.
DR GO; GO:0006508; P:proteolysis; TAS:ProtInc.
DR InterPro; IPR000177; Apple.
DR InterPro; IPR003014; PAN-1_domain.
DR InterPro; IPR003609; Pan_app.
DR InterPro; IPR001254; Peptidase_S1.
DR InterPro; IPR018114; Peptidase_S1_AS.
DR InterPro; IPR001314; Peptidase_S1A.
DR InterPro; IPR009003; Trypsin-like_Pept_dom.
DR Pfam; PF00024; PAN_1; 4.
DR Pfam; PF00089; Trypsin; 1.
DR PRINTS; PR00005; APPLEDOMAIN.
DR PRINTS; PR00722; CHYMOTRYPSIN.
DR SMART; SM00223; APPLE; 4.
DR SMART; SM00020; Tryp_SPc; 1.
DR SUPFAM; SSF50494; SSF50494; 1.
DR PROSITE; PS00495; APPLE; 4.
DR PROSITE; PS50948; PAN; 4.
DR PROSITE; PS50240; TRYPSIN_DOM; 1.
DR PROSITE; PS00134; TRYPSIN_HIS; 1.
DR PROSITE; PS00135; TRYPSIN_SER; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Blood coagulation; Complete proteome;
KW Direct protein sequencing; Disease mutation; Disulfide bond;
KW Fibrinolysis; Glycoprotein; Hemostasis; Hydrolase;
KW Inflammatory response; Polymorphism; Protease; Reference proteome;
KW Repeat; Secreted; Serine protease; Signal; Zymogen.
FT SIGNAL 1 19
FT CHAIN 20 390 Plasma kallikrein heavy chain.
FT /FTId=PRO_0000028021.
FT CHAIN 391 638 Plasma kallikrein light chain.
FT /FTId=PRO_0000028022.
FT DOMAIN 21 104 Apple 1.
FT DOMAIN 111 194 Apple 2.
FT DOMAIN 201 284 Apple 3.
FT DOMAIN 292 375 Apple 4.
FT DOMAIN 391 626 Peptidase S1.
FT ACT_SITE 434 434 Charge relay system.
FT ACT_SITE 483 483 Charge relay system.
FT ACT_SITE 578 578 Charge relay system.
FT CARBOHYD 127 127 N-linked (GlcNAc...).
FT CARBOHYD 308 308 N-linked (GlcNAc...).
FT CARBOHYD 396 396 N-linked (GlcNAc...).
FT CARBOHYD 453 453 N-linked (GlcNAc...).
FT CARBOHYD 494 494 N-linked (GlcNAc...).
FT DISULFID 21 104
FT DISULFID 47 77
FT DISULFID 51 57
FT DISULFID 111 194
FT DISULFID 137 166
FT DISULFID 141 147
FT DISULFID 201 284
FT DISULFID 227 256
FT DISULFID 231 237
FT DISULFID 292 375
FT DISULFID 318 347
FT DISULFID 322 328
FT DISULFID 340 345
FT DISULFID 383 503
FT DISULFID 419 435
FT DISULFID 517 584
FT DISULFID 548 563
FT DISULFID 574 602
FT VARIANT 123 123 G -> R (in PKK deficiency; reduces the
FT binding activity of Apple domain 2 to HMW
FT kininogen).
FT /FTId=VAR_054907.
FT VARIANT 143 143 N -> S (in PKK deficiency; reduces the
FT binding activity of Apple domain 2 to HMW
FT kininogen; dbSNP:rs3733402).
FT /FTId=VAR_013598.
FT VARIANT 178 178 A -> T (in dbSNP:rs4253257).
FT /FTId=VAR_016280.
FT VARIANT 202 202 H -> Q (in dbSNP:rs4253373).
FT /FTId=VAR_013599.
FT VARIANT 208 208 H -> P.
FT /FTId=VAR_013600.
FT VARIANT 210 210 A -> E (in dbSNP:rs2278542).
FT /FTId=VAR_020180.
FT VARIANT 269 269 S -> C (in dbSNP:rs4253376).
FT /FTId=VAR_016281.
FT VARIANT 311 311 F -> V (in dbSNP:rs4253377).
FT /FTId=VAR_016282.
FT VARIANT 358 358 T -> A (in dbSNP:rs4253379).
FT /FTId=VAR_016283.
FT VARIANT 381 381 S -> A (in dbSNP:rs4253301).
FT /FTId=VAR_016284.
FT VARIANT 442 442 Q -> P (in dbSNP:rs4253316).
FT /FTId=VAR_016285.
FT VARIANT 548 548 C -> Y (in PKK deficiency).
FT /FTId=VAR_054908.
FT VARIANT 560 560 R -> Q (in dbSNP:rs4253325).
FT /FTId=VAR_016286.
FT STRAND 405 425
FT STRAND 428 431
FT HELIX 433 436
FT HELIX 442 444
FT STRAND 445 448
FT HELIX 454 456
FT STRAND 466 471
FT STRAND 479 482
FT STRAND 485 491
FT HELIX 507 511
FT STRAND 515 523
FT STRAND 525 528
FT STRAND 536 543
FT HELIX 545 549
FT STRAND 561 564
FT STRAND 581 586
FT STRAND 589 598
FT STRAND 600 603
FT STRAND 609 613
FT HELIX 614 617
FT HELIX 618 625
SQ SEQUENCE 638 AA; 71370 MW; E62F9C1053838FB4 CRC64;
MILFKQATYF ISLFATVSCG CLTQLYENAF FRGGDVASMY TPNAQYCQMR CTFHPRCLLF
SFLPASSIND MEKRFGCFLK DSVTGTLPKV HRTGAVSGHS LKQCGHQISA CHRDIYKGVD
MRGVNFNVSK VSSVEECQKR CTNNIRCQFF SYATQTFHKA EYRNNCLLKY SPGGTPTAIK
VLSNVESGFS LKPCALSEIG CHMNIFQHLA FSDVDVARVL TPDAFVCRTI CTYHPNCLFF
TFYTNVWKIE SQRNVCLLKT SESGTPSSST PQENTISGYS LLTCKRTLPE PCHSKIYPGV
DFGGEELNVT FVKGVNVCQE TCTKMIRCQF FTYSLLPEDC KEEKCKCFLR LSMDGSPTRI
AYGTQGSSGY SLRLCNTGDN SVCTTKTSTR IVGGTNSSWG EWPWQVSLQV KLTAQRHLCG
GSLIGHQWVL TAAHCFDGLP LQDVWRIYSG ILNLSDITKD TPFSQIKEII IHQNYKVSEG
NHDIALIKLQ APLNYTEFQK PICLPSKGDT STIYTNCWVT GWGFSKEKGE IQNILQKVNI
PLVTNEECQK RYQDYKITQR MVCAGYKEGG KDACKGDSGG PLVCKHNGMW RLVGITSWGE
GCARREQPGV YTKVAEYMDW ILEKTQSSDG KAQMQSPA
//
MIM
229000
*RECORD*
*FIELD* NO
229000
*FIELD* TI
*229000 KALLIKREIN B, PLASMA, 1; KLKB1
;;PREKALLIKREIN; PPK;;
FLETCHER FACTOR;;
KLK3, FORMERLY
read more*FIELD* TX
CLONING
Chung et al. (1986) cloned a KLKB1 cDNA from a human liver cDNA library.
Analysis of the cDNA indicated that plasma prekallikrein is synthesized
as a precursor with a signal peptide of 19 amino acids. The mature form
the protein that circulates in blood is a single-chain polypeptide of
619 amino acids. Plasma prekallikrein is converted to plasma kallikrein
by factor XIIa (610619) by the cleavage of an internal arg-ile bond.
Plasma kallikrein is composed of a heavy chain (371 amino acids) and a
light chain (248 amino acids), which are held together by a disulfide
bond. The heavy chain originates from the N-terminal end of the zymogen
and contains 4 tandem repeats (apple domains) that contain 90 or 91
amino acids. The light chain of plasma kallikrein contains the catalytic
portion of the enzyme and is homologous to the trypsin family of serine
proteases. Prekallikrein and factor XI (264900) share 58% amino acid
sequence identity.
Wuepper (1973) and Weiss et al. (1974) presented evidence indicating
identity of Fletcher factor (Hathaway et al., 1965) and prekallikrein.
GENE FUNCTION
Tait and Fujikawa (1986) demonstrated that the kallikrein apple domains
(A1 to A4) mediate the high affinity binding of the enzyme to its major
substrate, high molecular weight kininogen (see 612358). Herwald et al.
(1996) showed that the kallikrein-kininogen complex binds to cell
surface receptors leading to the targeted action of bradykinin, the
product of kallikrein-mediated proteolysis.
GENE STRUCTURE
Beaubien et al. (1991) demonstrated that, like the F11 gene, the KLKB1
gene contains 15 exons. Beaubien et al. (1991) also demonstrated that
the gene organization of the catalytic subunit of KLKB1 is similar to
that of trypsin and other related serine proteases. The findings
suggested that plasma kallikrein and factor XI were derived from a
common ancestor through gene duplication.
MAPPING
By in situ hybridization, Beaubien et al. (1991) mapped the KLKB1 gene
to chromosome 4q35, where the F11 gene is located, and the mouse homolog
to chromosome 8.
MOLECULAR GENETICS
In a study of 591 African Americans with end-stage renal disease (ESRD)
and 139 African American control subjects, Yu et al. (2000) identified
12 allelic variants in the 5-prime proximal promoter and 7 exons of the
KLKB1 gene. One common polymorphism present in 30% of the study
population at position 521 of KLKB1 cDNA leads to the replacement of
asparagine with serine at codon 124 in the heavy chain of the A2 domain
of the protein. Several polymorphisms were found at a slightly increased
frequency among families with end-stage renal disease; however, none of
these associations was statistically significant. Yu et al. (2000) found
an association of certain alleles of 2 CA/GT repeat polymorphic markers
with ESRD in African Americans, but no causative mutation was
identified.
In a 79-year-old Caucasian male with prekallikrein (Fletcher factor)
deficiency (612423), Wynne Jones et al. (2004) identified a homozygous
arg94-to-ter substitution in the KLKB1 gene (R94X; 229000.0001).
HISTORY
For a history of the Fletcher factor, see 612423 and Giangrande (2003).
*FIELD* AV
.0001
PREKALLIKREIN DEFICIENCY
KLKB1, ARG94TER
In a 79-year-old Caucasian male with prekallikrein deficiency (612423)
whose parents were first cousins, Wynne Jones et al. (2004) identified a
homozygous 430C-T transition in exon 5 of the KLKB1 gene, resulting in
an arg94-to-ter (R94X) substitution. The patient presented with a
6-month history of stable exertional angina but otherwise had no
significant past medical history. Coronary angiography and coronary
artery bypass grafting were not complicated by abnormal bleeding;
however, he had prolongation of the activated partial thromboplastin
time (aPTT). Five heterozygous offspring of the proband each showed a
normal aPTT but reduced prekallikrein activity and antigen. This was the
first description of a kindred in which absence of expression of one or
both KLKB1 alleles was confirmed by genotype.
.0002
PREKALLIKREIN DEFICIENCY
KLKB1, TRP383TER
In a boy with extremely low prekallikrein activity and antigen (612423),
Lombardi et al. (2003) identified compound heterozygosity for 2
mutations in the KLKB1 gene: a 1298G-A transition in exon 11, resulting
in a trp383-to-ter (W383X) substitution, and a 1736G-A transition in
exon 14, resulting in a cys529-to-tyr (C529Y) substitution
(229000.0003). He inherited the former mutation from his father and the
latter mutation from his mother. The mutation was not found in 40
control subjects from the same geographic area. No associated
abnormality was apparent in the proband or his parents.
.0003
PREKALLIKREIN DEFICIENCY
KLKB1, CYS529TYR
See 229000.0002 and Lombardi et al. (2003).
.0004
PREKALLIKREIN DEFICIENCY
KLKB1, GLY104ARG
In 3 members of a Japanese family with plasma prekallikrein deficiency
(612423), Katsuda et al. (2007) identified homozygosity for 2 mutations
in exon 5 of the KLKB1 gene: a 438G-A transition resulting in a
gly104-to-arg (G104R) substitution, and a 499A-G transition resulting in
an asn124-to-ser (N124S) substitution (229000.0005). Both substitutions
occurred in the A2 domain of the heavy chain. The authors designated
this mutation PKD Seki. Using mutant A2 proteins in E. coli, Katsuda et
al. (2007) demonstrated that the 2 substitutions in the A2 domain reduce
the binding activity of A2 to high molecular weight kininogen,
suggesting that this binding may play a crucial role in the first step
of blood coagulation.
.0005
PREKALLIKREIN DEFICIENCY
KLKB1, ASN124SER
See 229000.0004 and Katsuda et al. (2007).
*FIELD* SA
Hathaway and Alsever (1970); Saito et al. (1972)
*FIELD* RF
1. Beaubien, G.; Rosinski-Chupin, I.; Mattei, M. G.; Mbikay, M.; Chretien,
M.; Seidah, N. G.: Gene structure and chromosomal localization of
plasma kallikrein. Biochemistry 30: 1628-1635, 1991.
2. Chung, D. W.; Fujikawa, K.; McMullen, B. A.; Davie, E. W.: Human
plasma prekallikrein, a zymogen to a serine protease that contains
four tandem repeats. Biochemistry 25: 2410-2417, 1986.
3. Giangrande, P. L. F.: Historical review: six characters in search
of an author: the history of the nomenclature of coagulation factors. Brit.
J. Haemat. 121: 703-712, 2003.
4. Hathaway, W. E.; Alsever, J.: The relation of 'Fletcher factor'
to factor XI and XII. Brit. J. Haemat. 18: 161-169, 1970.
5. Hathaway, W. E.; Belhasen, L. P.; Hathaway, H. S.: Evidence for
a new plasma thromboplastin factor. I. Case report, coagulation studies
and physiochemical properties. Blood 26: 521-532, 1965.
6. Herwald, H.; Dedio, J.; Kellner, R.; Loos, M.; Muller-Esterl, W.
: Isolation and characterization of the kininogen-binding protein
p33 from endothelial cells: identity with the gC1q receptor J. Biol.
Chem. 271: 13040-13047, 1996.
7. Katsuda, I.; Maruyama, F.; Ezaki, K.; Sawamura, T.; Ichihara, Y.
: A new type of plasma prekallikrein deficiency associated with homozygosity
for gly104arg and asn124ser in apple domain 2 of the heavy-chain region. Europ.
J. Haemat. 79: 59-68, 2007. Note: Erratum: Europ J. Haemat. 79: 185
only, 2007.
8. Lombardi, A. M.; Sartori, M. T.; Cabrio, L. Fadin, M.; Zanon, E.;
Girolami, A.: Severe prekallikrein (Fletcher factor) deficiency due
to a compound heterozygosis (383trp stop codon and cys529tyr). Thromb.
Haemost. 90: 1040-1045, 2003.
9. Saito, H.; Ratnoff, O. D.; Donaldson, V. H.; Abilgaard, C. C.;
Hattersley, P. G.: Fletcher factor. (Letter) Blood 39: 745-747,
1972.
10. Tait, J. F.; Fujikawa, K.: Identification of the binding site
for plasma prekallikrein in human high molecular weight kininogen:
a region from residues 185 to 224 of the kininogen light chain retains
full binding activity. J. Biol. Chem. 261: 15396-15401, 1986.
11. Weiss, A. S.; Gallin, J. I.; Kaplan, A.: Fletcher factor deficiency:
a diminished rate of Hageman factor activation caused by absence of
prekallikrein with abnormalities of coagulation, fibrinolysis, chemotactic
activity, and kinin generation. J. Clin. Invest. 53: 622-633, 1974.
12. Wuepper, K. D.: Prekallikrein deficiency in man. J. Exp. Med. 138:
1345-1355, 1973.
13. Wynne Jones, D.; Russell, G.; Allford, S. L.; Burdon, K.; Hawkins,
G. A.; Bowden, D. W.; Minaee, S.; Mumford, A. D.: Severe prekallikrein
deficiency associated with homozygosity for an arg94stop nonsense
mutation. Brit. J. Haemat. 127: 220-223, 2004.
14. Yu, H.; Anderson, P. J.; Freedman, B. I.; Rich, S. S.; Bowden,
D. W.: Genomic structure of the human plasma prekallikrein gene,
identification of allelic variants, and analysis in end-stage renal
disease. Genomics 69: 225-234, 2000.
*FIELD* CN
Carol A. Bocchini - updated: 11/20/2008
Victor A. McKusick - updated: 12/20/2004
Victor A. McKusick - updated: 9/4/2003
Ada Hamosh - updated: 1/3/2001
*FIELD* CD
Victor A. McKusick: 6/3/1986
*FIELD* ED
carol: 03/17/2009
terry: 12/1/2008
carol: 11/26/2008
carol: 11/20/2008
terry: 6/9/2005
tkritzer: 1/7/2005
terry: 12/20/2004
alopez: 3/17/2004
cwells: 9/30/2003
terry: 9/4/2003
carol: 1/7/2001
terry: 1/3/2001
carol: 4/27/1999
mark: 6/9/1995
mimadm: 2/19/1994
supermim: 3/16/1992
carol: 4/4/1991
carol: 3/28/1991
supermim: 3/20/1990
*RECORD*
*FIELD* NO
229000
*FIELD* TI
*229000 KALLIKREIN B, PLASMA, 1; KLKB1
;;PREKALLIKREIN; PPK;;
FLETCHER FACTOR;;
KLK3, FORMERLY
read more*FIELD* TX
CLONING
Chung et al. (1986) cloned a KLKB1 cDNA from a human liver cDNA library.
Analysis of the cDNA indicated that plasma prekallikrein is synthesized
as a precursor with a signal peptide of 19 amino acids. The mature form
the protein that circulates in blood is a single-chain polypeptide of
619 amino acids. Plasma prekallikrein is converted to plasma kallikrein
by factor XIIa (610619) by the cleavage of an internal arg-ile bond.
Plasma kallikrein is composed of a heavy chain (371 amino acids) and a
light chain (248 amino acids), which are held together by a disulfide
bond. The heavy chain originates from the N-terminal end of the zymogen
and contains 4 tandem repeats (apple domains) that contain 90 or 91
amino acids. The light chain of plasma kallikrein contains the catalytic
portion of the enzyme and is homologous to the trypsin family of serine
proteases. Prekallikrein and factor XI (264900) share 58% amino acid
sequence identity.
Wuepper (1973) and Weiss et al. (1974) presented evidence indicating
identity of Fletcher factor (Hathaway et al., 1965) and prekallikrein.
GENE FUNCTION
Tait and Fujikawa (1986) demonstrated that the kallikrein apple domains
(A1 to A4) mediate the high affinity binding of the enzyme to its major
substrate, high molecular weight kininogen (see 612358). Herwald et al.
(1996) showed that the kallikrein-kininogen complex binds to cell
surface receptors leading to the targeted action of bradykinin, the
product of kallikrein-mediated proteolysis.
GENE STRUCTURE
Beaubien et al. (1991) demonstrated that, like the F11 gene, the KLKB1
gene contains 15 exons. Beaubien et al. (1991) also demonstrated that
the gene organization of the catalytic subunit of KLKB1 is similar to
that of trypsin and other related serine proteases. The findings
suggested that plasma kallikrein and factor XI were derived from a
common ancestor through gene duplication.
MAPPING
By in situ hybridization, Beaubien et al. (1991) mapped the KLKB1 gene
to chromosome 4q35, where the F11 gene is located, and the mouse homolog
to chromosome 8.
MOLECULAR GENETICS
In a study of 591 African Americans with end-stage renal disease (ESRD)
and 139 African American control subjects, Yu et al. (2000) identified
12 allelic variants in the 5-prime proximal promoter and 7 exons of the
KLKB1 gene. One common polymorphism present in 30% of the study
population at position 521 of KLKB1 cDNA leads to the replacement of
asparagine with serine at codon 124 in the heavy chain of the A2 domain
of the protein. Several polymorphisms were found at a slightly increased
frequency among families with end-stage renal disease; however, none of
these associations was statistically significant. Yu et al. (2000) found
an association of certain alleles of 2 CA/GT repeat polymorphic markers
with ESRD in African Americans, but no causative mutation was
identified.
In a 79-year-old Caucasian male with prekallikrein (Fletcher factor)
deficiency (612423), Wynne Jones et al. (2004) identified a homozygous
arg94-to-ter substitution in the KLKB1 gene (R94X; 229000.0001).
HISTORY
For a history of the Fletcher factor, see 612423 and Giangrande (2003).
*FIELD* AV
.0001
PREKALLIKREIN DEFICIENCY
KLKB1, ARG94TER
In a 79-year-old Caucasian male with prekallikrein deficiency (612423)
whose parents were first cousins, Wynne Jones et al. (2004) identified a
homozygous 430C-T transition in exon 5 of the KLKB1 gene, resulting in
an arg94-to-ter (R94X) substitution. The patient presented with a
6-month history of stable exertional angina but otherwise had no
significant past medical history. Coronary angiography and coronary
artery bypass grafting were not complicated by abnormal bleeding;
however, he had prolongation of the activated partial thromboplastin
time (aPTT). Five heterozygous offspring of the proband each showed a
normal aPTT but reduced prekallikrein activity and antigen. This was the
first description of a kindred in which absence of expression of one or
both KLKB1 alleles was confirmed by genotype.
.0002
PREKALLIKREIN DEFICIENCY
KLKB1, TRP383TER
In a boy with extremely low prekallikrein activity and antigen (612423),
Lombardi et al. (2003) identified compound heterozygosity for 2
mutations in the KLKB1 gene: a 1298G-A transition in exon 11, resulting
in a trp383-to-ter (W383X) substitution, and a 1736G-A transition in
exon 14, resulting in a cys529-to-tyr (C529Y) substitution
(229000.0003). He inherited the former mutation from his father and the
latter mutation from his mother. The mutation was not found in 40
control subjects from the same geographic area. No associated
abnormality was apparent in the proband or his parents.
.0003
PREKALLIKREIN DEFICIENCY
KLKB1, CYS529TYR
See 229000.0002 and Lombardi et al. (2003).
.0004
PREKALLIKREIN DEFICIENCY
KLKB1, GLY104ARG
In 3 members of a Japanese family with plasma prekallikrein deficiency
(612423), Katsuda et al. (2007) identified homozygosity for 2 mutations
in exon 5 of the KLKB1 gene: a 438G-A transition resulting in a
gly104-to-arg (G104R) substitution, and a 499A-G transition resulting in
an asn124-to-ser (N124S) substitution (229000.0005). Both substitutions
occurred in the A2 domain of the heavy chain. The authors designated
this mutation PKD Seki. Using mutant A2 proteins in E. coli, Katsuda et
al. (2007) demonstrated that the 2 substitutions in the A2 domain reduce
the binding activity of A2 to high molecular weight kininogen,
suggesting that this binding may play a crucial role in the first step
of blood coagulation.
.0005
PREKALLIKREIN DEFICIENCY
KLKB1, ASN124SER
See 229000.0004 and Katsuda et al. (2007).
*FIELD* SA
Hathaway and Alsever (1970); Saito et al. (1972)
*FIELD* RF
1. Beaubien, G.; Rosinski-Chupin, I.; Mattei, M. G.; Mbikay, M.; Chretien,
M.; Seidah, N. G.: Gene structure and chromosomal localization of
plasma kallikrein. Biochemistry 30: 1628-1635, 1991.
2. Chung, D. W.; Fujikawa, K.; McMullen, B. A.; Davie, E. W.: Human
plasma prekallikrein, a zymogen to a serine protease that contains
four tandem repeats. Biochemistry 25: 2410-2417, 1986.
3. Giangrande, P. L. F.: Historical review: six characters in search
of an author: the history of the nomenclature of coagulation factors. Brit.
J. Haemat. 121: 703-712, 2003.
4. Hathaway, W. E.; Alsever, J.: The relation of 'Fletcher factor'
to factor XI and XII. Brit. J. Haemat. 18: 161-169, 1970.
5. Hathaway, W. E.; Belhasen, L. P.; Hathaway, H. S.: Evidence for
a new plasma thromboplastin factor. I. Case report, coagulation studies
and physiochemical properties. Blood 26: 521-532, 1965.
6. Herwald, H.; Dedio, J.; Kellner, R.; Loos, M.; Muller-Esterl, W.
: Isolation and characterization of the kininogen-binding protein
p33 from endothelial cells: identity with the gC1q receptor J. Biol.
Chem. 271: 13040-13047, 1996.
7. Katsuda, I.; Maruyama, F.; Ezaki, K.; Sawamura, T.; Ichihara, Y.
: A new type of plasma prekallikrein deficiency associated with homozygosity
for gly104arg and asn124ser in apple domain 2 of the heavy-chain region. Europ.
J. Haemat. 79: 59-68, 2007. Note: Erratum: Europ J. Haemat. 79: 185
only, 2007.
8. Lombardi, A. M.; Sartori, M. T.; Cabrio, L. Fadin, M.; Zanon, E.;
Girolami, A.: Severe prekallikrein (Fletcher factor) deficiency due
to a compound heterozygosis (383trp stop codon and cys529tyr). Thromb.
Haemost. 90: 1040-1045, 2003.
9. Saito, H.; Ratnoff, O. D.; Donaldson, V. H.; Abilgaard, C. C.;
Hattersley, P. G.: Fletcher factor. (Letter) Blood 39: 745-747,
1972.
10. Tait, J. F.; Fujikawa, K.: Identification of the binding site
for plasma prekallikrein in human high molecular weight kininogen:
a region from residues 185 to 224 of the kininogen light chain retains
full binding activity. J. Biol. Chem. 261: 15396-15401, 1986.
11. Weiss, A. S.; Gallin, J. I.; Kaplan, A.: Fletcher factor deficiency:
a diminished rate of Hageman factor activation caused by absence of
prekallikrein with abnormalities of coagulation, fibrinolysis, chemotactic
activity, and kinin generation. J. Clin. Invest. 53: 622-633, 1974.
12. Wuepper, K. D.: Prekallikrein deficiency in man. J. Exp. Med. 138:
1345-1355, 1973.
13. Wynne Jones, D.; Russell, G.; Allford, S. L.; Burdon, K.; Hawkins,
G. A.; Bowden, D. W.; Minaee, S.; Mumford, A. D.: Severe prekallikrein
deficiency associated with homozygosity for an arg94stop nonsense
mutation. Brit. J. Haemat. 127: 220-223, 2004.
14. Yu, H.; Anderson, P. J.; Freedman, B. I.; Rich, S. S.; Bowden,
D. W.: Genomic structure of the human plasma prekallikrein gene,
identification of allelic variants, and analysis in end-stage renal
disease. Genomics 69: 225-234, 2000.
*FIELD* CN
Carol A. Bocchini - updated: 11/20/2008
Victor A. McKusick - updated: 12/20/2004
Victor A. McKusick - updated: 9/4/2003
Ada Hamosh - updated: 1/3/2001
*FIELD* CD
Victor A. McKusick: 6/3/1986
*FIELD* ED
carol: 03/17/2009
terry: 12/1/2008
carol: 11/26/2008
carol: 11/20/2008
terry: 6/9/2005
tkritzer: 1/7/2005
terry: 12/20/2004
alopez: 3/17/2004
cwells: 9/30/2003
terry: 9/4/2003
carol: 1/7/2001
terry: 1/3/2001
carol: 4/27/1999
mark: 6/9/1995
mimadm: 2/19/1994
supermim: 3/16/1992
carol: 4/4/1991
carol: 3/28/1991
supermim: 3/20/1990
MIM
612423
*RECORD*
*FIELD* NO
612423
*FIELD* TI
#612423 PREKALLIKREIN DEFICIENCY
;;PKK DEFICIENCY;;
FLETCHER FACTOR DEFICIENCY
*FIELD* TX
read moreA number sign (#) is used with this entry because prekallikrein
(Fletcher factor) deficiency is caused by mutation in the KLKB1 gene
(229000).
CLINICAL FEATURES
Hathaway et al. (1965) described a Kentucky kindred in which 4 sibs of
the name Fletcher showed a previously undescribed coagulation defect.
Although they had no abnormal bleeding tendency, their blood showed much
prolonged activated partial thromboplastin time (aPTT) and delayed
thromboplastin generation but normal prothrombin time. Plasmas deficient
in factors VIII (300841), IX (300746), XI (264900), and XII (610619)
corrected the abnormality. Further studies by Hathaway et al. (1976)
suggested that severe prekallikrein deficiency has no clinically
significant effect on hemostasis, fibrinolysis, inflammatory responses,
or leukocyte function.
Hattersley and Hayse (1970) reported 3 unrelated cases. Research by
Saito et al. (1972) suggests that Fletcher factor deficiency is
associated with an inhibitor to the clot-promoting activities of
glass-like surfaces.
Aznar et al. (1978) observed the abnormality in 3 sisters of a
Mediterranean family. The parents were related. Two of the 3 sisters
plus a brother without clotting abnormality had arthrogryposis multiplex
congenita. A preponderant occurrence in black families had been
suggested previously on the basis of 6 families.
Kyrle et al. (1984) studied a case of severe PKK deficiency and
identified the heterozygous state in 8 relatives. The possibility of
relationship to the Graves disease in the proband was raised.
Bouma et al. (1986) reported 3 sibs with the genetic compound state. The
father had deficient clotting activity and normal ratio of antigen to
activity. The mother had a variant prekallikrein, dubbed Long Beach,
with elevated ratio of antigen to activity, i.e., a CRM+ variant.
DeLa Cadena (1995) reported studies of a 9-year-old patient with
markedly prolonged aPTT but normal prothrombin time and bleeding time.
The prolonged aPTT was due to a PKK deficiency. DeLa Cadena (1995) also
reviewed the role of prekallikrein in thrombosis.
INHERITANCE
Raffoux et al. (1982) found evidence for autosomal recessive inheritance
and no suggestion of linkage with HLA.
MOLECULAR GENETICS
In a 79-year-old Caucasian male with prekallikrein deficiency, Wynne
Jones et al. (2004) identified a homozygous arg94-to-ter substitution in
the KLKB1 gene (R94X; 229000.0001).
HISTORY
Giangrande (2003) provided a history of the Fletcher factor. In the
winter of 1963 the mountain cabin of the Fletcher family in eastern
Kentucky was destroyed by fire. Several members of the family were
admitted to the hospital because of exposure to severe cold and
frostbite. During this period of hospitalization, an 11-year-old female
member of the family was deemed to require adenoidectomy. Abnormal
results were observed on routine coagulation tests and she was referred
to the University of Kentucky for investigation (Hathaway et al., 1965).
Three other sibs were also found to have similar laboratory results,
although there was no personal or family history suggestive of a
bleeding disorder.
Wuepper (1973) and Weiss et al. (1974) presented evidence indicating
identity of Fletcher factor and prekallikrein.
*FIELD* SA
Poon et al. (1982); Saito et al. (1981); Sollo and Saleem (1985);
Yu et al. (2000)
*FIELD* RF
1. Aznar, J. A.; Espana, F.; Aznar, J.; Tascon, A.; Jimenez, C.:
Fletcher factor deficiency: report of a new family. Scand. J. Haemat. 21:
94-98, 1978.
2. Bouma, B. N.; Kerbiriou, D. M.; Baker, J.; Griffin, J. H.: Characterization
of a variant prekallikrein, prekallikrein Long Beach, from a family
with mixed cross-reacting material--positive and cross-reacting material--negative
prekallikrein deficiency. J. Clin. Invest. 78: 170-176, 1986.
3. DeLa Cadena, R. A.: Fletcher factor deficiency in a 9-year-old
girl: mechanisms of the contact pathway of blood coagulation. Am.
J. Hemat. 48: 273-277, 1995.
4. Giangrande, P. L. F.: Historical review: six characters in search
of an author: the history of the nomenclature of coagulation factors. Brit.
J. Haemat. 121: 703-712, 2003.
5. Hathaway, W. E.; Belhasen, L. P.; Hathaway, H. S.: Evidence for
a new plasma thromboplastin factor. I. Case report, coagulation studies
and physiochemical properties. Blood 26: 521-532, 1965.
6. Hathaway, W. E.; Wuepper, K. D.; Weston, W. L.; Humbert, J. R.;
Rivers, R. P. A.; Genton, E.; August, C. S.; Montgomery, R. R.; Mass,
M. F.: Clinical and psychologic studies of two siblings with prekallikrein
(Fletcher factor) deficiency. Am. J. Med. 60: 654-664, 1976.
7. Hattersley, P. G.; Hayse, D.: Fletcher factor deficiency: a report
of three unrelated cases. Brit. J. Haemat. 18: 411-416, 1970.
8. Kyrle, P. A.; Niessner, H.; Deutsch, E.; Lechner, K.; Korninger,
C.; Mannhalter, C.: CRM+ severe Fletcher factor deficiency associated
with Graves' disease. Haemostasis 14: 302-306, 1984.
9. Poon, M.-C.; Moore, M. R.; Castleberry, R. P.; Lurie, A.; Huang,
S. T.; Lehmeyer, J.: Severe Fletcher factor (plasma prekallikrein)
deficiency with partial deficiency of Hageman factor (factor XII):
report of a case with observation on in vivo and in vitro leukocyte
chemotaxis. Am. J. Hemat. 12: 261-270, 1982.
10. Raffoux, C.; Alexandre, P.; Perrier, P.; Briquel, M. E.; Streiff,
F.: HLA typing in a new family with Fletcher factor deficiency. Hum.
Genet. 60: 71-73, 1982.
11. Saito, H.; Goodnough, L. T.; Soria, J.; Soria, C.; Aznar, J.;
Espana, F.: Heterogeneity of human prekallikrein deficiency (Fletcher
trait): evidence that five of 18 cases are positive for cross-reacting
material. New Eng. J. Med. 305: 910-914, 1981.
12. Saito, H.; Ratnoff, O. D.; Donaldson, V. H.; Abilgaard, C. C.;
Hattersley, P. G.: Fletcher factor. (Letter) Blood 39: 745-747,
1972.
13. Sollo, D. G.; Saleem, A.: Prekallikrein (Fletcher factor) deficiency. Ann.
Clin. Lab. Sci. 15: 279-285, 1985.
14. Weiss, A. S.; Gallin, J. I.; Kaplan, A.: Fletcher factor deficiency:
a diminished rate of Hageman factor activation caused by absence of
prekallikrein with abnormalities of coagulation, fibrinolysis, chemotactic
activity, and kinin generation. J. Clin. Invest. 53: 622-633, 1974.
15. Wuepper, K. D.: Prekallikrein deficiency in man. J. Exp. Med. 138:
1345-1355, 1973.
16. Wynne Jones, D.; Russell, G.; Allford, S. L.; Burdon, K.; Hawkins,
G. A.; Bowden, D. W.; Minaee, S.; Mumford, A. D.: Severe prekallikrein
deficiency associated with homozygosity for an arg94stop nonsense
mutation. Brit. J. Haemat. 127: 220-223, 2004.
17. Yu, H.; Anderson, P. J.; Freedman, B. I.; Rich, S. S.; Bowden,
D. W.: Genomic structure of the human plasma prekallikrein gene,
identification of allelic variants, and analysis in end-stage renal
disease. Genomics 69: 225-234, 2000.
*FIELD* CD
Carol A. Bocchini: 11/20/2008
*FIELD* ED
carol: 04/07/2011
carol: 11/20/2008
*RECORD*
*FIELD* NO
612423
*FIELD* TI
#612423 PREKALLIKREIN DEFICIENCY
;;PKK DEFICIENCY;;
FLETCHER FACTOR DEFICIENCY
*FIELD* TX
read moreA number sign (#) is used with this entry because prekallikrein
(Fletcher factor) deficiency is caused by mutation in the KLKB1 gene
(229000).
CLINICAL FEATURES
Hathaway et al. (1965) described a Kentucky kindred in which 4 sibs of
the name Fletcher showed a previously undescribed coagulation defect.
Although they had no abnormal bleeding tendency, their blood showed much
prolonged activated partial thromboplastin time (aPTT) and delayed
thromboplastin generation but normal prothrombin time. Plasmas deficient
in factors VIII (300841), IX (300746), XI (264900), and XII (610619)
corrected the abnormality. Further studies by Hathaway et al. (1976)
suggested that severe prekallikrein deficiency has no clinically
significant effect on hemostasis, fibrinolysis, inflammatory responses,
or leukocyte function.
Hattersley and Hayse (1970) reported 3 unrelated cases. Research by
Saito et al. (1972) suggests that Fletcher factor deficiency is
associated with an inhibitor to the clot-promoting activities of
glass-like surfaces.
Aznar et al. (1978) observed the abnormality in 3 sisters of a
Mediterranean family. The parents were related. Two of the 3 sisters
plus a brother without clotting abnormality had arthrogryposis multiplex
congenita. A preponderant occurrence in black families had been
suggested previously on the basis of 6 families.
Kyrle et al. (1984) studied a case of severe PKK deficiency and
identified the heterozygous state in 8 relatives. The possibility of
relationship to the Graves disease in the proband was raised.
Bouma et al. (1986) reported 3 sibs with the genetic compound state. The
father had deficient clotting activity and normal ratio of antigen to
activity. The mother had a variant prekallikrein, dubbed Long Beach,
with elevated ratio of antigen to activity, i.e., a CRM+ variant.
DeLa Cadena (1995) reported studies of a 9-year-old patient with
markedly prolonged aPTT but normal prothrombin time and bleeding time.
The prolonged aPTT was due to a PKK deficiency. DeLa Cadena (1995) also
reviewed the role of prekallikrein in thrombosis.
INHERITANCE
Raffoux et al. (1982) found evidence for autosomal recessive inheritance
and no suggestion of linkage with HLA.
MOLECULAR GENETICS
In a 79-year-old Caucasian male with prekallikrein deficiency, Wynne
Jones et al. (2004) identified a homozygous arg94-to-ter substitution in
the KLKB1 gene (R94X; 229000.0001).
HISTORY
Giangrande (2003) provided a history of the Fletcher factor. In the
winter of 1963 the mountain cabin of the Fletcher family in eastern
Kentucky was destroyed by fire. Several members of the family were
admitted to the hospital because of exposure to severe cold and
frostbite. During this period of hospitalization, an 11-year-old female
member of the family was deemed to require adenoidectomy. Abnormal
results were observed on routine coagulation tests and she was referred
to the University of Kentucky for investigation (Hathaway et al., 1965).
Three other sibs were also found to have similar laboratory results,
although there was no personal or family history suggestive of a
bleeding disorder.
Wuepper (1973) and Weiss et al. (1974) presented evidence indicating
identity of Fletcher factor and prekallikrein.
*FIELD* SA
Poon et al. (1982); Saito et al. (1981); Sollo and Saleem (1985);
Yu et al. (2000)
*FIELD* RF
1. Aznar, J. A.; Espana, F.; Aznar, J.; Tascon, A.; Jimenez, C.:
Fletcher factor deficiency: report of a new family. Scand. J. Haemat. 21:
94-98, 1978.
2. Bouma, B. N.; Kerbiriou, D. M.; Baker, J.; Griffin, J. H.: Characterization
of a variant prekallikrein, prekallikrein Long Beach, from a family
with mixed cross-reacting material--positive and cross-reacting material--negative
prekallikrein deficiency. J. Clin. Invest. 78: 170-176, 1986.
3. DeLa Cadena, R. A.: Fletcher factor deficiency in a 9-year-old
girl: mechanisms of the contact pathway of blood coagulation. Am.
J. Hemat. 48: 273-277, 1995.
4. Giangrande, P. L. F.: Historical review: six characters in search
of an author: the history of the nomenclature of coagulation factors. Brit.
J. Haemat. 121: 703-712, 2003.
5. Hathaway, W. E.; Belhasen, L. P.; Hathaway, H. S.: Evidence for
a new plasma thromboplastin factor. I. Case report, coagulation studies
and physiochemical properties. Blood 26: 521-532, 1965.
6. Hathaway, W. E.; Wuepper, K. D.; Weston, W. L.; Humbert, J. R.;
Rivers, R. P. A.; Genton, E.; August, C. S.; Montgomery, R. R.; Mass,
M. F.: Clinical and psychologic studies of two siblings with prekallikrein
(Fletcher factor) deficiency. Am. J. Med. 60: 654-664, 1976.
7. Hattersley, P. G.; Hayse, D.: Fletcher factor deficiency: a report
of three unrelated cases. Brit. J. Haemat. 18: 411-416, 1970.
8. Kyrle, P. A.; Niessner, H.; Deutsch, E.; Lechner, K.; Korninger,
C.; Mannhalter, C.: CRM+ severe Fletcher factor deficiency associated
with Graves' disease. Haemostasis 14: 302-306, 1984.
9. Poon, M.-C.; Moore, M. R.; Castleberry, R. P.; Lurie, A.; Huang,
S. T.; Lehmeyer, J.: Severe Fletcher factor (plasma prekallikrein)
deficiency with partial deficiency of Hageman factor (factor XII):
report of a case with observation on in vivo and in vitro leukocyte
chemotaxis. Am. J. Hemat. 12: 261-270, 1982.
10. Raffoux, C.; Alexandre, P.; Perrier, P.; Briquel, M. E.; Streiff,
F.: HLA typing in a new family with Fletcher factor deficiency. Hum.
Genet. 60: 71-73, 1982.
11. Saito, H.; Goodnough, L. T.; Soria, J.; Soria, C.; Aznar, J.;
Espana, F.: Heterogeneity of human prekallikrein deficiency (Fletcher
trait): evidence that five of 18 cases are positive for cross-reacting
material. New Eng. J. Med. 305: 910-914, 1981.
12. Saito, H.; Ratnoff, O. D.; Donaldson, V. H.; Abilgaard, C. C.;
Hattersley, P. G.: Fletcher factor. (Letter) Blood 39: 745-747,
1972.
13. Sollo, D. G.; Saleem, A.: Prekallikrein (Fletcher factor) deficiency. Ann.
Clin. Lab. Sci. 15: 279-285, 1985.
14. Weiss, A. S.; Gallin, J. I.; Kaplan, A.: Fletcher factor deficiency:
a diminished rate of Hageman factor activation caused by absence of
prekallikrein with abnormalities of coagulation, fibrinolysis, chemotactic
activity, and kinin generation. J. Clin. Invest. 53: 622-633, 1974.
15. Wuepper, K. D.: Prekallikrein deficiency in man. J. Exp. Med. 138:
1345-1355, 1973.
16. Wynne Jones, D.; Russell, G.; Allford, S. L.; Burdon, K.; Hawkins,
G. A.; Bowden, D. W.; Minaee, S.; Mumford, A. D.: Severe prekallikrein
deficiency associated with homozygosity for an arg94stop nonsense
mutation. Brit. J. Haemat. 127: 220-223, 2004.
17. Yu, H.; Anderson, P. J.; Freedman, B. I.; Rich, S. S.; Bowden,
D. W.: Genomic structure of the human plasma prekallikrein gene,
identification of allelic variants, and analysis in end-stage renal
disease. Genomics 69: 225-234, 2000.
*FIELD* CD
Carol A. Bocchini: 11/20/2008
*FIELD* ED
carol: 04/07/2011
carol: 11/20/2008