RBCC Red Blood Cell Collection

PKLR (PK1, PKL) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Pyruvate kinase PKLR; 2.7.1.40 (Pyruvate kinase 1; Pyruvate kinase isozymes L/R; R-type/L-type pyruvate kinase; Red cell/liver pyruvate kinase)
Note: presumably soluble (membrane word is not in UniProt keywords or features)

hRBCD IPI00027165
IPI00027165 Splice Isoform 1 Of Pyruvate kinase, isozymes R/L glycolysis last step, pyruvate kinase activity, red-cell and liver soluble n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a n/a cytoplasmic SILIGAPGGPAGYLR found at its expected molecular weight found at molecular weight

UniProt P30613
ID KPYR_HUMAN Reviewed; 574 AA.
AC P30613; P11973;
DT 01-APR-1993, integrated into UniProtKB/Swiss-Prot.
read moreDT 30-MAY-2000, sequence version 2.
DT 22-JAN-2014, entry version 167.
DE RecName: Full=Pyruvate kinase PKLR;
DE EC=2.7.1.40;
DE AltName: Full=Pyruvate kinase 1;
DE AltName: Full=Pyruvate kinase isozymes L/R;
DE AltName: Full=R-type/L-type pyruvate kinase;
DE AltName: Full=Red cell/liver pyruvate kinase;
GN Name=PKLR; Synonyms=PK1, PKL;
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], AND VARIANT PKRD MET-384.
RX PubMed=1896471; DOI=10.1073/pnas.88.18.8218;
RA Kanno H., Fujii H., Hirono A., Miwa S.;
RT "cDNA cloning of human R-type pyruvate kinase and identification of a
RT single amino acid substitution (Thr384-->Met) affecting enzymatic
RT stability in a pyruvate kinase variant (PK Tokyo) associated with
RT hereditary hemolytic anemia.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:8218-8221(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=3126495; DOI=10.1073/pnas.85.6.1792;
RA Tani K., Fujii H., Nagata S., Miwa S.;
RT "Human liver type pyruvate kinase: complete amino acid sequence and
RT the expression in mammalian cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 85:1792-1795(1988).
RN [3]
RP SEQUENCE REVISION TO 130 AND 232.
RA Kanno H.;
RL Submitted (JUL-1998) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT ILE-506.
RG NIEHS SNPs program;
RL Submitted (JUN-2003) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM R-TYPE).
RC TISSUE=Pancreas;
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 [6]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 470-574.
RX PubMed=3566732; DOI=10.1016/0006-291X(87)91372-6;
RA Tani K., Fujii H., Tsutsumi H., Sukegawa J., Toyoshima K.,
RA Yoshida M.C., Noguchi T., Tanaka T., Miwa S.;
RT "Human liver type pyruvate kinase: cDNA cloning and chromosomal
RT assignment.";
RL Biochem. Biophys. Res. Commun. 143:431-438(1987).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 365-431, AND VARIANT PKRD PHE-368.
RX PubMed=8476433; DOI=10.1006/bbrc.1993.1379;
RA Kanno H., Fujii H., Tsujino G., Miwa S.;
RT "Molecular basis of impaired pyruvate kinase isozyme conversion in
RT erythroid cells: a single amino acid substitution near the active site
RT and decreased mRNA content of the R-type PK.";
RL Biochem. Biophys. Res. Commun. 192:46-52(1993).
RN [8]
RP REVIEW ON VARIANTS.
RX PubMed=8664896;
RX DOI=10.1002/(SICI)1098-1004(1996)7:1<1::AID-HUMU1>3.3.CO;2-J;
RA Beutler E., Baronciani L.;
RT "Mutations in pyruvate kinase.";
RL Hum. Mutat. 7:1-6(1996).
RN [9]
RP REVIEW ON VARIANTS.
RX PubMed=8807089; DOI=10.1006/bcmd.1996.0012;
RA Baronciani L., Bianchi P., Zanella A.;
RT "Hematologically important mutations: red cell pyruvate kinase.";
RL Blood Cells Mol. Dis. 22:85-89(1996).
RN [10]
RP REVIEW ON VARIANTS.
RX PubMed=9075576; DOI=10.1006/bcmd.1996.0107;
RA Baronciani L., Bianchi P., Zanella A.;
RT "Hematologically important mutations: red cell pyruvate kinase (1st
RT update).";
RL Blood Cells Mol. Dis. 22:259-264(1996).
RN [11]
RP REVIEW ON VARIANTS.
RX PubMed=10087985; DOI=10.1006/bcmd.1998.0193;
RA Baronciani L., Bianchi P., Zanella A.;
RT "Hematologically important mutations: red cell pyruvate kinase (2nd
RT update).";
RL Blood Cells Mol. Dis. 24:273-279(1998).
RN [12]
RP REVIEW ON VARIANTS.
RX PubMed=10772876; DOI=10.1006/bcmd.2000.0276;
RA Bianchi P., Zanella A.;
RT "Hematologically important mutations: red cell pyruvate kinase (third
RT update).";
RL Blood Cells Mol. Dis. 26:47-53(2000).
RN [13]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.73 ANGSTROMS) OF 47-574 IN COMPLEX WITH
RP FRUCTOSE 1,6-BISPHOSPHATE, ALLOSTERIC ACTIVATION, ENZYME REGULATION,
RP CHARACTERIZATION OF VARIANTS PKRD SER-332; ASP-364; ASN-390; HIS-479;
RP TRP-486; LEU-504 AND TRP-532, CHARACTERIZATION OF VARIANT MET-384, AND
RP SUBUNIT.
RX PubMed=11960989; DOI=10.1074/jbc.M202107200;
RA Valentini G., Chiarelli L.R., Fortin R., Dolzan M., Galizzi A.,
RA Abraham D.J., Wang C., Bianchi P., Zanella A., Mattevi A.;
RT "Structure and function of human erythrocyte pyruvate kinase.
RT Molecular basis of nonspherocytic hemolytic anemia.";
RL J. Biol. Chem. 277:23807-23814(2002).
RN [15]
RP VARIANTS PKRD CYS-163 AND MET-384.
RX PubMed=2018831;
RA Neubauer B., Lakomek M., Winkler H., Parke M., Hofferbert S.,
RA Schroter W.;
RT "Point mutations in the L-type pyruvate kinase gene of two children
RT with hemolytic anemia caused by pyruvate kinase deficiency.";
RL Blood 77:1871-1875(1991).
RN [16]
RP VARIANT PKRD LYS-421.
RX PubMed=1536957;
RA Kanno H., Fujii H., Hirono A., Omine M., Miwa S.;
RT "Identical point mutations of the R-type pyruvate kinase (PK) cDNA
RT found in unrelated PK variants associated with hereditary hemolytic
RT anemia.";
RL Blood 79:1347-1350(1992).
RN [17]
RP VARIANT PKRD GLN-426.
RX PubMed=8481523;
RA Kanno H., Fujii H., Miwa S.;
RT "Low substrate affinity of pyruvate kinase variant (PK Sapporo) caused
RT by a single amino acid substitution (426 Arg-->Gln) associated with
RT hereditary hemolytic anemia.";
RL Blood 81:2439-2441(1993).
RN [18]
RP VARIANTS PKRD ASP-134; PRO-155; HIS-359; TRP-486; VAL-495 AND GLN-510.
RX PubMed=8483951; DOI=10.1073/pnas.90.9.4324;
RA Baronciani L., Beutler E.;
RT "Analysis of pyruvate kinase-deficiency mutations that produce
RT nonspherocytic hemolytic anemia.";
RL Proc. Natl. Acad. Sci. U.S.A. 90:4324-4327(1993).
RN [19]
RP VARIANT PKRD HIS-479.
RX PubMed=8161798;
RA Kanno H., Ballas S.K., Miwa S., Fujii H., Bowman H.S.;
RT "Molecular abnormality of erythrocyte pyruvate kinase deficiency in
RT the Amish.";
RL Blood 83:2311-2316(1994).
RN [20]
RP VARIANTS PKRD SER-332; SER-336; LYS-354 DEL; ASP-361; THR-392;
RP HIS-498; GLN-510 AND TRP-532.
RX PubMed=8180378;
RA Lenzner C., Nuernberg P., Thiele B.-J., Reis A., Brabec V.,
RA Sakalova A., Jacobasch G.;
RT "Mutations in the pyruvate kinase L gene in patients with hereditary
RT hemolytic anemia.";
RL Blood 83:2817-2822(1994).
RN [21]
RP VARIANTS PKRD GLU-331; ALA-341; LYS-393; SER-393; ASP-458; MET-460 AND
RP HIS-498.
RX PubMed=7706479; DOI=10.1172/JCI117846;
RA Baronciani L., Beutler E.;
RT "Molecular study of pyruvate kinase deficient patients with hereditary
RT nonspherocytic hemolytic anemia.";
RL J. Clin. Invest. 95:1702-1709(1995).
RN [22]
RP VARIANTS PKRD.
RA Baronciani L., Westwood B., Beutler E.;
RT "Study of the molecular defects in pyruvate kinase (PK) deficient
RT patients affected by hereditary nonspherocytic hemolytic anemia
RT (HNHA).";
RL J. Invest. Med. 43:341A-341A(1995).
RN [23]
RP VARIANT PKHYP GLU-37.
RX PubMed=9090535;
RX DOI=10.1002/(SICI)1098-1004(1997)9:3<282::AID-HUMU13>3.3.CO;2-0;
RA Beutler E., Westwood B., van Zwieten R., Roos D.;
RT "G-to-T transition at cDNA nt 110 (K37Q) in the PKLR (pyruvate kinase)
RT gene is the molecular basis of a case of hereditary increase of red
RT blood cell ATP.";
RL Hum. Mutat. 9:282-285(1997).
RN [24]
RP VARIANTS PKRD GLN-172; GLN-337; HIS-339; THR-357; ILE-408; THR-431;
RP TRP-486 AND GLN-532.
RX PubMed=9827908; DOI=10.1046/j.1365-2141.1998.01013.x;
RA Zarza R., Alvarez R., Pujades A., Nomdedeu B., Carrera A., Estella J.,
RA Remacha A., Sanchez J.M., Morey M., Cortes T., Perez Lungmus G.,
RA Bureo E., Vives Corrons J.L.;
RT "Molecular characterization of the PK-LR gene in pyruvate kinase
RT deficient Spanish patients.";
RL Br. J. Haematol. 103:377-382(1998).
RN [25]
RP VARIANT PKRD TYR-130.
RX PubMed=9886305; DOI=10.1046/j.1365-2141.1998.01094.x;
RA Cohen-Solal M., Prehu C., Wajcman H., Poyart C.,
RA Bardakdjian-Michau J., Kister J., Prome D., Valentin C., Bachir D.,
RA Galacteros F.;
RT "A new sickle cell disease phenotype associating Hb S trait, severe
RT pyruvate kinase deficiency (PK Conakry), and an alpha-2 globin gene
RT variant (Hb Conakry).";
RL Br. J. Haematol. 103:950-956(1998).
RN [26]
RP VARIANTS PKRD SER-332; PRO-337; TRP-486; CYS-498 AND GLN-510.
RX PubMed=9482576;
RX DOI=10.1002/(SICI)1098-1004(1998)11:2<127::AID-HUMU5>3.3.CO;2-P;
RA Pastore L., della Morte R., Frisso G., Alfinito F., Vitale D.,
RA Calise R.M., Ferraro F., Zagari A., Rotoli B., Salvatore F.;
RT "Novel mutations and structural implications in R-type pyruvate
RT kinase-deficient patients from Southern Italy.";
RL Hum. Mutat. 11:127-134(1998).
RN [27]
RP VARIANTS PKRD MET-335; LYS-348 DEL; GLY-387; ASP-394 AND VAL-394.
RX PubMed=11328279; DOI=10.1046/j.1365-2141.2001.02711.x;
RA Zanella A., Bianchi P., Fermo E., Iurlo A., Zappa M., Vercellati C.,
RA Boschetti C., Baronciani L., Cotton F.;
RT "Molecular characterization of the PK-LR gene in sixteen pyruvate
RT kinase-deficient patients.";
RL Br. J. Haematol. 113:43-48(2001).
RN [28]
RP VARIANTS PKRD TRP-40; 48-THR--THR-53 DEL; PRO-73; ASN-90; ARG-111;
RP THR-154; LEU-163; VAL-165; VAL-272; ASN-310; LEU-320; GLU-358 AND
RP PRO-374.
RX PubMed=19085939; DOI=10.1002/humu.20915;
RA van Wijk R., Huizinga E.G., van Wesel A.C.W., van Oirschot B.A.,
RA Hadders M.A., van Solinge W.W.;
RT "Fifteen novel mutations in PKLR associated with pyruvate kinase (PK)
RT deficiency: structural implications of amino acid substitutions in
RT PK.";
RL Hum. Mutat. 30:446-453(2009).
RN [29]
RP VARIANTS PKRD ALA-341 AND GLN-569.
RX PubMed=21794208;
RA Lyon G.J., Jiang T., Van Wijk R., Wang W., Bodily P.M., Xing J.,
RA Tian L., Robison R.J., Clement M., Lin Y., Zhang P., Liu Y., Moore B.,
RA Glessner J.T., Elia J., Reimherr F., van Solinge W.W., Yandell M.,
RA Hakonarson H., Wang J., Johnson W.E., Wei Z., Wang K.;
RT "Exome sequencing and unrelated findings in the context of complex
RT disease research: ethical and clinical implications.";
RL Discov. Med. 12:41-55(2011).
CC -!- FUNCTION: Plays a key role in glycolysis (By similarity).
CC -!- CATALYTIC ACTIVITY: ATP + pyruvate = ADP + phosphoenolpyruvate.
CC -!- COFACTOR: Magnesium.
CC -!- COFACTOR: Potassium.
CC -!- ENZYME REGULATION: Allosterically activated by fructose 1,6-
CC bisphosphate.
CC -!- PATHWAY: Carbohydrate degradation; glycolysis; pyruvate from D-
CC glyceraldehyde 3-phosphate: step 5/5.
CC -!- SUBUNIT: Homotetramer.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=R-type; Synonyms=PKR;
CC IsoId=P30613-1; Sequence=Displayed;
CC Name=L-type; Synonyms=PKL;
CC IsoId=P30613-2; Sequence=VSP_002883;
CC -!- DISEASE: Pyruvate kinase hyperactivity (PKHYP) [MIM:102900]:
CC Autosomal dominant phenotype characterized by increase of red
CC blood cell ATP. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- DISEASE: Pyruvate kinase deficiency of red cells (PKRD)
CC [MIM:266200]: A frequent cause of hereditary non-spherocytic
CC hemolytic anemia. Clinically, pyruvate kinase-deficient patients
CC suffer from a highly variable degree of chronic hemolysis, ranging
CC from severe neonatal jaundice and fatal anemia at birth, severe
CC transfusion-dependent chronic hemolysis, moderate hemolysis with
CC exacerbation during infection, to a fully compensated hemolysis
CC without apparent anemia. Note=The disease is caused by mutations
CC affecting the gene represented in this entry.
CC -!- MISCELLANEOUS: There are 4 isozymes of pyruvate kinase in mammals:
CC L, R, M1 and M2. L type is major isozyme in the liver, R is found
CC in red cells, M1 is the main form in muscle, heart and brain, and
CC M2 is found in early fetal tissues.
CC -!- SIMILARITY: Belongs to the pyruvate kinase family.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/PKLR";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/pklr/";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Pyruvate kinase entry;
CC URL="http://en.wikipedia.org/wiki/Pyruvate_kinase";
CC -!- WEB RESOURCE: Name=PKLR Mutation Database;
CC URL="http://www.pklrmutationdatabase.com/";
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DR EMBL; AB015983; BAA31706.1; -; mRNA.
DR EMBL; M15465; AAA60104.1; -; mRNA.
DR EMBL; AY316591; AAP69527.1; -; Genomic_DNA.
DR EMBL; BC025737; AAH25737.1; -; mRNA.
DR EMBL; S60712; AAB26262.1; -; mRNA.
DR PIR; I52269; KIHUPR.
DR RefSeq; NP_000289.1; NM_000298.5.
DR RefSeq; NP_870986.1; NM_181871.3.
DR UniGene; Hs.95990; -.
DR PDB; 2VGB; X-ray; 2.73 A; A/B/C/D=47-574.
DR PDB; 2VGF; X-ray; 2.75 A; A/B/C/D=47-574.
DR PDB; 2VGG; X-ray; 2.74 A; A/B/C/D=47-574.
DR PDB; 2VGI; X-ray; 2.87 A; A/B/C/D=47-574.
DR PDB; 4IMA; X-ray; 1.95 A; A/B/C/D=34-574.
DR PDB; 4IP7; X-ray; 1.80 A; A/B/C/D=34-574.
DR PDBsum; 2VGB; -.
DR PDBsum; 2VGF; -.
DR PDBsum; 2VGG; -.
DR PDBsum; 2VGI; -.
DR PDBsum; 4IMA; -.
DR PDBsum; 4IP7; -.
DR ProteinModelPortal; P30613; -.
DR SMR; P30613; 57-573.
DR IntAct; P30613; 4.
DR STRING; 9606.ENSP00000339933; -.
DR ChEMBL; CHEMBL1075126; -.
DR DrugBank; DB00119; Pyruvic acid.
DR PhosphoSite; P30613; -.
DR DMDM; 8247933; -.
DR REPRODUCTION-2DPAGE; P30613; -.
DR SWISS-2DPAGE; P30613; -.
DR PaxDb; P30613; -.
DR PRIDE; P30613; -.
DR DNASU; 5313; -.
DR Ensembl; ENST00000342741; ENSP00000339933; ENSG00000143627.
DR Ensembl; ENST00000392414; ENSP00000376214; ENSG00000143627.
DR Ensembl; ENST00000571194; ENSP00000461487; ENSG00000262785.
DR Ensembl; ENST00000572740; ENSP00000459921; ENSG00000262785.
DR GeneID; 5313; -.
DR KEGG; hsa:5313; -.
DR UCSC; uc001fkb.4; human.
DR CTD; 5313; -.
DR GeneCards; GC01M155259; -.
DR HGNC; HGNC:9020; PKLR.
DR HPA; CAB034376; -.
DR HPA; CAB034378; -.
DR MIM; 102900; phenotype.
DR MIM; 266200; phenotype.
DR MIM; 609712; gene.
DR neXtProt; NX_P30613; -.
DR Orphanet; 766; Hemolytic anemia due to red cell pyruvate kinase deficiency.
DR PharmGKB; PA33352; -.
DR eggNOG; COG0469; -.
DR HOGENOM; HOG000021559; -.
DR HOVERGEN; HBG000941; -.
DR KO; K12406; -.
DR OMA; IHTIVKV; -.
DR BioCyc; MetaCyc:HS07088-MONOMER; -.
DR Reactome; REACT_111045; Developmental Biology.
DR Reactome; REACT_111217; Metabolism.
DR SABIO-RK; P30613; -.
DR UniPathway; UPA00109; UER00188.
DR EvolutionaryTrace; P30613; -.
DR GeneWiki; PKLR; -.
DR GenomeRNAi; 5313; -.
DR NextBio; 20542; -.
DR PMAP-CutDB; P30613; -.
DR PRO; PR:P30613; -.
DR ArrayExpress; P30613; -.
DR Bgee; P30613; -.
DR CleanEx; HS_PKLR; -.
DR Genevestigator; P30613; -.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0000287; F:magnesium ion binding; IEA:InterPro.
DR GO; GO:0030955; F:potassium ion binding; IEA:InterPro.
DR GO; GO:0004743; F:pyruvate kinase activity; TAS:ProtInc.
DR GO; GO:0006754; P:ATP biosynthetic process; IEA:Ensembl.
DR GO; GO:0032869; P:cellular response to insulin stimulus; IEA:Ensembl.
DR GO; GO:0031018; P:endocrine pancreas development; TAS:Reactome.
DR GO; GO:0006112; P:energy reserve metabolic process; TAS:Reactome.
DR GO; GO:0006096; P:glycolysis; TAS:Reactome.
DR GO; GO:0031325; P:positive regulation of cellular metabolic process; TAS:Reactome.
DR GO; GO:0042866; P:pyruvate biosynthetic process; IEA:Ensembl.
DR GO; GO:0033198; P:response to ATP; IEA:Ensembl.
DR GO; GO:0051591; P:response to cAMP; IEA:Ensembl.
DR GO; GO:0009749; P:response to glucose stimulus; IEA:Ensembl.
DR GO; GO:0009408; P:response to heat; IEA:Ensembl.
DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl.
DR GO; GO:0010226; P:response to lithium ion; IEA:Ensembl.
DR GO; GO:0007584; P:response to nutrient; IEA:Ensembl.
DR GO; GO:0051707; P:response to other organism; IEA:Ensembl.
DR GO; GO:0044281; P:small molecule metabolic process; TAS:Reactome.
DR Gene3D; 2.40.33.10; -; 1.
DR Gene3D; 3.20.20.60; -; 2.
DR Gene3D; 3.40.1380.20; -; 1.
DR InterPro; IPR001697; Pyr_Knase.
DR InterPro; IPR015813; Pyrv/PenolPyrv_Kinase-like_dom.
DR InterPro; IPR011037; Pyrv_Knase-like_insert_dom.
DR InterPro; IPR015794; Pyrv_Knase_a/b.
DR InterPro; IPR018209; Pyrv_Knase_AS.
DR InterPro; IPR015793; Pyrv_Knase_brl.
DR InterPro; IPR015795; Pyrv_Knase_C.
DR InterPro; IPR015806; Pyrv_Knase_insert_dom.
DR PANTHER; PTHR11817; PTHR11817; 1.
DR Pfam; PF00224; PK; 1.
DR Pfam; PF02887; PK_C; 1.
DR PRINTS; PR01050; PYRUVTKNASE.
DR SUPFAM; SSF50800; SSF50800; 1.
DR SUPFAM; SSF51621; SSF51621; 2.
DR SUPFAM; SSF52935; SSF52935; 1.
DR TIGRFAMs; TIGR01064; pyruv_kin; 1.
DR PROSITE; PS00110; PYRUVATE_KINASE; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Allosteric enzyme; Alternative splicing; ATP-binding;
KW Complete proteome; Disease mutation; Glycolysis;
KW Hereditary hemolytic anemia; Kinase; Magnesium; Metal-binding;
KW Nucleotide-binding; Polymorphism; Potassium; Pyruvate;
KW Reference proteome; Transferase.
FT CHAIN 1 574 Pyruvate kinase PKLR.
FT /FTId=PRO_0000112094.
FT REGION 475 480 Allosteric activator binding.
FT REGION 559 564 Allosteric activator binding.
FT METAL 118 118 Potassium.
FT METAL 120 120 Potassium.
FT METAL 156 156 Potassium.
FT METAL 157 157 Potassium; via carbonyl oxygen.
FT METAL 315 315 Magnesium.
FT METAL 339 339 Magnesium.
FT BINDING 116 116 Substrate.
FT BINDING 338 338 Substrate; via amide nitrogen.
FT BINDING 339 339 Substrate; via amide nitrogen.
FT BINDING 371 371 Substrate.
FT BINDING 525 525 Allosteric activator.
FT BINDING 532 532 Allosteric activator.
FT SITE 313 313 Transition state stabilizer (By
FT similarity).
FT VAR_SEQ 1 33 MSIQENISSLQLRSWVSKSQRDLAKSILIGAPG -> ME
FT (in isoform L-type).
FT /FTId=VSP_002883.
FT VARIANT 37 37 G -> E (in PKHYP).
FT /FTId=VAR_011435.
FT VARIANT 40 40 R -> W (in PKRD).
FT /FTId=VAR_058467.
FT VARIANT 48 53 Missing (in PKRD).
FT /FTId=VAR_058468.
FT VARIANT 73 73 L -> P (in PKRD).
FT /FTId=VAR_058469.
FT VARIANT 80 80 S -> P (in PKRD).
FT /FTId=VAR_011436.
FT VARIANT 86 86 R -> P (in PKRD).
FT /FTId=VAR_011437.
FT VARIANT 90 90 I -> N (in PKRD).
FT /FTId=VAR_011438.
FT VARIANT 95 95 G -> R (in PKRD).
FT /FTId=VAR_011439.
FT VARIANT 107 107 M -> T (in PKRD).
FT /FTId=VAR_004028.
FT VARIANT 111 111 G -> R (in PKRD).
FT /FTId=VAR_011440.
FT VARIANT 115 115 A -> P (in PKRD; Val de Marne).
FT /FTId=VAR_011441.
FT VARIANT 120 120 S -> F (in PKRD; Beaujon).
FT /FTId=VAR_011442.
FT VARIANT 130 130 S -> Y (in PKRD; Conakry).
FT /FTId=VAR_011443.
FT VARIANT 131 131 Missing (in PKRD).
FT /FTId=VAR_004029.
FT VARIANT 134 134 V -> D (in PKRD).
FT /FTId=VAR_004030.
FT VARIANT 153 153 I -> T (in PKRD).
FT /FTId=VAR_011474.
FT VARIANT 154 154 A -> T (in PKRD).
FT /FTId=VAR_058470.
FT VARIANT 155 155 L -> P (in PKRD).
FT /FTId=VAR_004031.
FT VARIANT 159 159 G -> V (in PKRD).
FT /FTId=VAR_011444.
FT VARIANT 163 163 R -> C (in PKRD; Linz).
FT /FTId=VAR_004033.
FT VARIANT 163 163 R -> L (in PKRD).
FT /FTId=VAR_058471.
FT VARIANT 165 165 G -> V (in PKRD).
FT /FTId=VAR_058472.
FT VARIANT 172 172 E -> Q (in PKRD; Sassari).
FT /FTId=VAR_004032.
FT VARIANT 219 219 I -> T (in PKRD).
FT /FTId=VAR_011475.
FT VARIANT 221 221 D -> DD (in PKRD).
FT /FTId=VAR_004034.
FT VARIANT 222 222 G -> A (in PKRD; Katsushika).
FT /FTId=VAR_011445.
FT VARIANT 263 263 G -> R (in PKRD).
FT /FTId=VAR_011447.
FT VARIANT 263 263 G -> W (in PKRD).
FT /FTId=VAR_011448.
FT VARIANT 272 272 L -> V (in PKRD).
FT /FTId=VAR_058473.
FT VARIANT 275 275 G -> R (in PKRD).
FT /FTId=VAR_004035.
FT VARIANT 281 281 D -> N (in PKRD).
FT /FTId=VAR_004036.
FT VARIANT 287 287 F -> V (in PKRD).
FT /FTId=VAR_004037.
FT VARIANT 288 288 V -> L (in PKRD; Moriguchi).
FT /FTId=VAR_011449.
FT VARIANT 293 293 D -> N (in PKRD).
FT /FTId=VAR_011446.
FT VARIANT 295 295 A -> V (in PKRD).
FT /FTId=VAR_011450.
FT VARIANT 310 310 I -> N (in PKRD; Dordrecht).
FT /FTId=VAR_011451.
FT VARIANT 314 314 I -> T (in PKRD; Hong Kong).
FT /FTId=VAR_004038.
FT VARIANT 315 315 E -> K (in PKRD).
FT /FTId=VAR_011452.
FT VARIANT 320 320 V -> L (in PKRD).
FT /FTId=VAR_058474.
FT VARIANT 331 331 D -> E (in PKRD; Parma).
FT /FTId=VAR_004039.
FT VARIANT 331 331 D -> N (in PKRD).
FT /FTId=VAR_011453.
FT VARIANT 332 332 G -> S (in PKRD; loss of catalytical
FT activity).
FT /FTId=VAR_004040.
FT VARIANT 335 335 V -> M (in PKRD).
FT /FTId=VAR_011476.
FT VARIANT 336 336 A -> S (in PKRD).
FT /FTId=VAR_004041.
FT VARIANT 337 337 R -> P (in PKRD).
FT /FTId=VAR_004042.
FT VARIANT 337 337 R -> Q (in PKRD).
FT /FTId=VAR_004043.
FT VARIANT 339 339 D -> H (in PKRD).
FT /FTId=VAR_004044.
FT VARIANT 341 341 G -> A (in PKRD).
FT /FTId=VAR_004045.
FT VARIANT 341 341 G -> D (in PKRD).
FT /FTId=VAR_011454.
FT VARIANT 342 342 I -> F (in PKRD).
FT /FTId=VAR_011455.
FT VARIANT 348 348 K -> N (in PKRD; Kamata).
FT /FTId=VAR_011456.
FT VARIANT 348 348 Missing (in PKRD; Brescia).
FT /FTId=VAR_011457.
FT VARIANT 352 352 A -> D (in PKRD).
FT /FTId=VAR_011477.
FT VARIANT 354 354 Missing (in PKRD).
FT /FTId=VAR_004046.
FT VARIANT 357 357 I -> T (in PKRD).
FT /FTId=VAR_004047.
FT VARIANT 358 358 G -> E (in PKRD).
FT /FTId=VAR_058475.
FT VARIANT 359 359 R -> C (in PKRD; Aomori).
FT /FTId=VAR_004048.
FT VARIANT 359 359 R -> H (in PKRD).
FT /FTId=VAR_004049.
FT VARIANT 361 361 N -> D (in PKRD).
FT /FTId=VAR_004050.
FT VARIANT 364 364 G -> D (in PKRD; Tjaereborg; unstability
FT of the protein and decrease in catalytic
FT activity).
FT /FTId=VAR_011458.
FT VARIANT 368 368 V -> F (in PKRD; Osaka).
FT /FTId=VAR_004051.
FT VARIANT 374 374 L -> P (in PKRD).
FT /FTId=VAR_058476.
FT VARIANT 376 376 S -> I (in PKRD).
FT /FTId=VAR_011459.
FT VARIANT 384 384 T -> M (in PKRD; Tokyo/Beirut; most
FT common mutation in Japanese population;
FT no conformational change).
FT /FTId=VAR_004052.
FT VARIANT 385 385 R -> W (in PKRD).
FT /FTId=VAR_011478.
FT VARIANT 387 387 E -> G (in PKRD).
FT /FTId=VAR_011460.
FT VARIANT 390 390 D -> N (in PKRD; Mantova; almost complete
FT inactivation).
FT /FTId=VAR_011461.
FT VARIANT 392 392 A -> T (in PKRD).
FT /FTId=VAR_004053.
FT VARIANT 393 393 N -> K (in PKRD).
FT /FTId=VAR_004054.
FT VARIANT 393 393 N -> S (in PKRD; Paris).
FT /FTId=VAR_004055.
FT VARIANT 394 394 A -> D (in PKRD).
FT /FTId=VAR_011462.
FT VARIANT 394 394 A -> V (in PKRD).
FT /FTId=VAR_011463.
FT VARIANT 401 401 C -> CS (in PKRD).
FT /FTId=VAR_004056.
FT VARIANT 408 408 T -> A (in PKRD; Hirosaki).
FT /FTId=VAR_011464.
FT VARIANT 408 408 T -> I (in PKRD).
FT /FTId=VAR_004057.
FT VARIANT 421 421 Q -> K (in PKRD; Fukushima/Maebashi/
FT Sendai).
FT /FTId=VAR_004058.
FT VARIANT 426 426 R -> Q (in PKRD; Sapporo).
FT /FTId=VAR_004059.
FT VARIANT 426 426 R -> W (in PKRD; Naniwa).
FT /FTId=VAR_004060.
FT VARIANT 427 427 E -> A (in PKRD).
FT /FTId=VAR_011465.
FT VARIANT 427 427 E -> D (in PKRD).
FT /FTId=VAR_011466.
FT VARIANT 431 431 A -> T (in PKRD).
FT /FTId=VAR_004061.
FT VARIANT 458 458 G -> D (in PKRD).
FT /FTId=VAR_004062.
FT VARIANT 459 459 A -> V (in PKRD).
FT /FTId=VAR_004063.
FT VARIANT 460 460 V -> M (in PKRD).
FT /FTId=VAR_004064.
FT VARIANT 468 468 A -> G (in PKRD).
FT /FTId=VAR_011479.
FT VARIANT 468 468 A -> V (in PKRD; Hadano).
FT /FTId=VAR_004065.
FT VARIANT 477 477 T -> A (in PKRD).
FT /FTId=VAR_011467.
FT VARIANT 479 479 R -> H (in PKRD; Amish; no conformational
FT change).
FT /FTId=VAR_011480.
FT VARIANT 485 485 S -> F (in PKRD).
FT /FTId=VAR_011468.
FT VARIANT 486 486 R -> W (in PKRD; frequent mutation; no
FT conformational change;
FT dbSNP:rs116100695).
FT /FTId=VAR_004066.
FT VARIANT 488 488 R -> Q (in PKRD).
FT /FTId=VAR_011469.
FT VARIANT 490 490 R -> W (in PKRD; dbSNP:rs200133000).
FT /FTId=VAR_004067.
FT VARIANT 495 495 A -> T (in PKRD).
FT /FTId=VAR_011470.
FT VARIANT 495 495 A -> V (in PKRD).
FT /FTId=VAR_004068.
FT VARIANT 498 498 R -> C (in PKRD).
FT /FTId=VAR_004069.
FT VARIANT 498 498 R -> H (in PKRD).
FT /FTId=VAR_004070.
FT VARIANT 504 504 R -> L (in PKRD; instability of the
FT protein; dbSNP:rs185753709).
FT /FTId=VAR_011471.
FT VARIANT 506 506 V -> I (in dbSNP:rs8177988).
FT /FTId=VAR_018848.
FT VARIANT 510 510 R -> Q (in PKRD; the most common mutation
FT in European population;
FT dbSNP:rs113403872).
FT /FTId=VAR_004071.
FT VARIANT 511 511 G -> R (in PKRD).
FT /FTId=VAR_011472.
FT VARIANT 531 531 R -> C (in PKRD).
FT /FTId=VAR_011473.
FT VARIANT 532 532 R -> Q (in PKRD).
FT /FTId=VAR_004072.
FT VARIANT 532 532 R -> W (in PKRD; Complete loss in the
FT responsiveness to fructose 1,6-
FT bisphosphate, FBP).
FT /FTId=VAR_004073.
FT VARIANT 552 552 V -> M (in PKRD).
FT /FTId=VAR_004074.
FT VARIANT 557 557 G -> A (in PKRD).
FT /FTId=VAR_011481.
FT VARIANT 559 559 R -> G (in PKRD).
FT /FTId=VAR_004075.
FT VARIANT 566 566 N -> K (in PKRD).
FT /FTId=VAR_004076.
FT VARIANT 569 569 R -> Q (in PKRD; dbSNP:rs61755431).
FT /FTId=VAR_011482.
FT CONFLICT 423 423 A -> R (in Ref. 2; AAA60104).
FT TURN 49 51
FT HELIX 55 57
FT HELIX 61 64
FT HELIX 69 74
FT STRAND 88 93
FT TURN 96 98
FT HELIX 101 110
FT STRAND 112 118
FT HELIX 124 139
FT TURN 140 143
FT HELIX 145 147
FT STRAND 152 156
FT STRAND 162 164
FT STRAND 170 172
FT STRAND 175 177
FT STRAND 182 186
FT HELIX 189 191
FT STRAND 199 203
FT HELIX 207 210
FT STRAND 216 219
FT TURN 220 223
FT STRAND 224 232
FT STRAND 235 242
FT STRAND 244 246
FT STRAND 251 253
FT HELIX 266 277
FT STRAND 281 285
FT HELIX 291 301
FT HELIX 303 305
FT STRAND 309 314
FT HELIX 317 321
FT HELIX 323 329
FT STRAND 330 336
FT HELIX 337 343
FT HELIX 346 348
FT HELIX 349 363
FT STRAND 367 372
FT HELIX 375 378
FT HELIX 385 397
FT STRAND 400 405
FT HELIX 406 409
FT HELIX 414 430
FT HELIX 434 442
FT HELIX 451 466
FT STRAND 469 474
FT STRAND 476 478
FT HELIX 479 485
FT STRAND 490 498
FT HELIX 500 505
FT HELIX 506 508
FT STRAND 512 516
FT HELIX 525 542
FT STRAND 551 561
FT STRAND 565 572
SQ SEQUENCE 574 AA; 61830 MW; 3B430896832032F5 CRC64;
MSIQENISSL QLRSWVSKSQ RDLAKSILIG APGGPAGYLR RASVAQLTQE LGTAFFQQQQ
LPAAMADTFL EHLCLLDIDS EPVAARSTSI IATIGPASRS VERLKEMIKA GMNIARLNFS
HGSHEYHAES IANVREAVES FAGSPLSYRP VAIALDTKGP EIRTGILQGG PESEVELVKG
SQVLVTVDPA FRTRGNANTV WVDYPNIVRV VPVGGRIYID DGLISLVVQK IGPEGLVTQV
ENGGVLGSRK GVNLPGAQVD LPGLSEQDVR DLRFGVEHGV DIVFASFVRK ASDVAAVRAA
LGPEGHGIKI ISKIENHEGV KRFDEILEVS DGIMVARGDL GIEIPAEKVF LAQKMMIGRC
NLAGKPVVCA TQMLESMITK PRPTRAETSD VANAVLDGAD CIMLSGETAK GNFPVEAVKM
QHAIAREAEA AVYHRQLFEE LRRAAPLSRD PTEVTAIGAV EAAFKCCAAA IIVLTTTGRS
AQLLSRYRPR AAVIAVTRSA QAARQVHLCR GVFPLLYREP PEAIWADDVD RRVQFGIESG
KLRGFLRVGD LVIVVTGWRP GSGYTNIMRV LSIS
//

MIM 102900
*RECORD*
*FIELD* NO
102900
*FIELD* TI
#102900 ADENOSINE TRIPHOSPHATE, ELEVATED, OF ERYTHROCYTES
;;PYRUVATE KINASE HYPERACTIVITY
read more*FIELD* TX
A number sign (#) is used with this entry because of evidence that the
phenotype of hereditary increase of red blood cell ATP is caused by a
specific mutation in the gene for red cell pyruvate kinase (PKLR;
609712.0008).

Brewer (1965) in the United States and Zurcher et al. (1965) in Holland
described high erythrocyte adenosine triphosphate as a dominantly
inherited trait. 'High red cell ATP syndrome' may be a heterogeneous
category. For example, pyrimidine-5-prime-nucleotidase deficiency
(266120) hemolytic anemia shows this feature. Max-Audit et al. (1980)
described a family in which 4 persons had polycythemia and pyruvate
kinase hyperactivity. They showed low 2,3-diphosphoglycerate (2,3-DPG)
and high adenosine triphosphate (ATP) levels. The PK electrophoretic
patterns in these persons were abnormal by the presence of several
additional bands.

Beutler et al. (1997) restudied the family described by Zurcher et al.
(1965) and by SSCP analysis found a band shift in exon 2 of the red cell
pyruvate kinase gene resulting from a point mutation at nucleotide 110.
Beutler (1997) verified the mutation as a G-to-A transition resulting in
a gly37-to-glu amino acid substitution (609712.0008). The mutation was
present in heterozygous state. Beutler et al. (1997) stated it is
possible that different mutations in the PKLR gene are responsible for
the finding in other families with elevated red cell ATP levels, because
the enzyme kinetics in other families have been different from those in
the family reported by Zurcher et al. (1965).

*FIELD* SA
Loos et al. (1967)
*FIELD* RF
1. Beutler, E.: Personal Communication. La Jolla, Calif. 5/13/1997.

2. Beutler, E.; Westwood, B.; van Zwieten, R.; Roos, D.: G-to-T transition
(sic) at cDNA nt 110 (K37Q) in the PKLR (pyruvate kinase) gene is
the molecular basis of a case of hereditary increase of red blood
cell ATP. Hum. Mutat. 9: 282-285, 1997.

3. Brewer, G. J.: A new inherited abnormality of human erythrocyte--elevated
erythrocyte adenosine triphosphate. Biochem. Biophys. Res. Commun. 18:
430-434, 1965.

4. Loos, J. A.; Prins, H. K.; Zurcher, C.: Elevated ATP levels in
human erythrocytes.In: Beutler, E.: Hereditary Disorders of Erythrocyte
Metabolism. New York: Grune and Stratton (pub.) 1967.

5. Max-Audit, I.; Rosa, R.; Marie, J.: Pyruvate kinase hyperactivity
genetically determined: metabolic consequences and molecular characterization. Blood 56:
902-909, 1980.

6. Zurcher, C.; Loos, J. A.; Prins, H. K.: Hereditary high ATP content
of human erythrocytes. Folia Haemat. 83: 366-376, 1965.

*FIELD* CS

Heme:
Polycythemia

Lab:
High erythrocyte adenosine triphosphate;
Pyruvate kinase hyperactivity;
Low 2,3-diphosphoglycerate (2,3-DPG);
Additional PK electrophoretic bands

Inheritance:
Autosomal dominant

*FIELD* CN
Victor A. McKusick - updated: 5/15/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 11/18/2005
mark: 5/15/1997
mark: 5/9/1997
alopez: 5/6/1997
mimadm: 3/11/1994
supermim: 3/16/1992
carol: 8/23/1990
supermim: 3/20/1990
ddp: 10/26/1989
marie: 3/25/1988

MIM 266200
*RECORD*
*FIELD* NO
266200
*FIELD* TI
#266200 PYRUVATE KINASE DEFICIENCY OF RED CELLS
;;PYRUVATE KINASE DEFICIENCY OF ERYTHROCYTE;;
read morePK DEFICIENCY
*FIELD* TX
A number sign (#) is used with this entry because red cell pyruvate
kinase (PK) deficiency is caused by mutation in the gene encoding
pyruvate kinase (PKLR; 609712).

DESCRIPTION

Red cell pyruvate kinase deficiency is the most common cause of
hereditary nonspherocytic hemolytic anemia. PK deficiency is also the
most frequent enzyme abnormality of the glycolytic pathway (Zanella et
al., 2005).

CLINICAL FEATURES

Valentine et al. (1961) first reported pyruvate kinase deficiency in 3
patients with congenital nonspherocytic hemolytic anemia. Tanaka et al.
(1962) observed a compensated hemolytic anemia in young adults who had
been relatively little incapacitated. At that time, separate alleles or
even genes at different loci were thought to be the possible bases for
clinical variability.

Bowman and Procopio (1963) observed a severe form of hemolytic anemia in
the Old Order Amish of Mifflin Co., Pennsylvania. The disorder was much
more severe than that reported by Tanaka et al. (1962), leading to death
in the first years of life if not treated by transfusions and
splenectomy. One of the Amish patients with PK deficiency hemolytic
anemia and splenectomy at age 30 months had persistent thrombocytosis
and carotid artery thromboses (Ginter, 1974).

Necheles et al. (1966) illustrated the clinical variability of PK
deficiency in 2 unrelated patients. One had cholecystitis and
cholelithiasis for which surgery was performed at age 23. He was well
thereafter until age 28 when anemia developed, for which splenectomy was
performed with good results. The second case was an infant who required
exchange transfusion in the neonatal period because of jaundice and
anemia. Results of splenectomy, performed at 14 months, were excellent.
Zuelzer et al. (1968) noted marked intrafamilial clinical variability,
which studies suggested was due to heterozygosity for 2 distinct
interacting mutants in mildly affected relatives of severely affected
probands. Persons possibly heterozygous for an anomalous pyruvate kinase
had anemia in the family reported by Sachs et al. (1968).

Etiemble et al. (1984) reported a family in which hemolytic anemia due
to red cell PK deficiency behaved as a seemingly autosomal dominant
trait. In affected members, residual PK activity was about 20% of
normal, an unusually low level for heterozygotes. The anemia was mild
except in the proband, a 2-year-old boy with severe anemia. Etiemble et
al. (1984) suggested that the presence of one or more mutated subunits
in the tetrameric form of L-type PK may lead to inactivation of these
tetramers. The greater severity in the proband was considered merely
part of a spectrum of expression of the same defect.

Gilsanz et al. (1993) reported PK deficiency as a cause of fetal anemia
and nonimmune hydrops fetalis. They described a woman in whom 3 previous
pregnancies had resulted in stillbirth or early neonatal death due to
anemic hydrops fetalis; PK deficiency was diagnosed in a later pregnancy
by umbilical vessel sampling at 30 weeks' gestation. The infant survived
with transfusion-dependent hemolytic anemia.

BIOCHEMICAL FEATURES

Koler et al. (1964) found that patients with PK deficiency in red blood
cells had normal PK activity in white blood cells, suggesting that the 2
enzymes were encoded by different loci.

Paglia et al. (1968) and Sachs et al. (1968) both reported families with
familial hemolytic anemia and postulated an inherited molecular lesion
of red cell PK. Both groups identified kinetically abnormal PK isozymes
that were associated with premature hemolysis. Bigley and Koler (1968)
found decreased liver PK activity in a patient with hemolytic anemia due
to red cell PK deficiency. The findings further suggested that the 2
enzymes are identical and likely derived from a common gene.

Boivin and Galand (1974) reported a mutant human red cell PK that showed
high affinity for the substrate phosphoenolpyruvate (PEP). Shinohara et
al. (1976) described a new pyruvate kinase variant, PK Osaka, and
discussed the various PK isozymes and their nomenclature. The variant
was ascertained through a patient with PK deficiency hemolytic anemia. A
genetic compound for 2 different PK mutations was studied by Zanella et
al. (1978).

The International Committee for Standardization in Haematology (1979)
provided recommended methods for the characterization and nomenclature
of red cell pyruvate kinase variants.

Variant pyruvate kinase enzymes isolated from patients with PK
deficiency were reported by many groups, including Vives-Corrons et al.
(1980), Kahn et al. (1981), Lakomek et al. (1983), Dente et al. (1982),
Paglia et al. (1983, 1983), and Schroter et al. (1982). The enzymes were
characterized by variable changes, including low activity, low substrate
affinity, high sensitivity to allosteric activation, thermolability,
aberrant kinetic properties, abnormal electrophoretic patterns, and
decreased antigenic concentrations.

Etiemble et al. (1982) described a new variant of erythrocyte PK
associated with severe hemolytic anemia. In contrast to previously
reported cases, the molecular abnormalities could not be detected in a
liver specimen.

In 2 of 651 unrelated patients with nonspherocytic hemolytic anemia,
Beutler et al. (1987) observed elevated red cell PK activities
commensurate with the decreased mean red cell age, but the residual PK
had marked kinetic abnormalities. Accumulation of metabolic
intermediates before pyruvate kinase and reduced levels of enzyme
activity of the red blood cells in the parents of both patients
supported the diagnosis of inherited PK abnormality as the cause of the
hemolytic anemia.

In 2 unrelated patients, the offspring of consanguineous parents, Tani
et al. (1988) identified PK variants associated with enzyme deficiency
and nonspherocytic hemolytic anemia. The variants were called PK Sendai
and PK Shinshu. Valentine et al. (1988) characterized the PK Greensboro
variant. Findings suggested that although heterozygotes may have
abnormal PK function, they may not have clinical manifestations or
hemolysis.

MOLECULAR GENETICS

In 2 Japanese patients, born of consanguineous parents, with hereditary
hemolytic anemia due to pyruvate kinase deficiency, Kanno et al. (1991)
identified a homozygous mutation in the PKLR gene (609712.0004).
Larochelle et al. (1991) identified a mutation in the PKLR gene
(609712.0001) in French Canadian patients with pyruvate kinase
deficiency.

Baronciani and Beutler (1995) found 19 different mutations among 58 of
60 PKLR alleles in 30 unrelated patients with hereditary nonspherocytic
hemolytic anemia due to PK deficiency. Miwa and Fujii (1996) tabulated
47 mutations in the PK gene known to result in hereditary hemolytic
anemia. Rouger et al. (1996) identified 7 different PK mutations in 26
unrelated families in France; 5 of these had not previously been
described. Beutler and Baronciani (1996) found that in all 55 different
mutations that had been described in patients with PK-deficient
hemolytic anemia, the mutations were widely distributed, occurring
throughout exons 4 to 12 in this 12-exon gene. Baronciani et al. (1996)
tabulated 59 different mutations in red cell pyruvate kinase of
hematologic importance.

In 23 patients from 21 unrelated families with PK deficiency, Fermo et
al. (2005) identified a total of 27 different mutations in the PKLR
gene, including 17 novel mutations. In a detailed review of PK
deficiency, Zanella et al. (2005) stated that more than 150 different
PKLR mutations had been identified.

Pissard et al. (2006) identified 41 different mutations in the PKLR
gene, including 27 novel mutations, among 56 French families with PK
deficiency. Most cases were ascertained because of neonatal or chronic
anemia; 2 cases were lethal in the neonatal period.

DIAGNOSIS

- Prenatal Diagnosis

Baronciani and Beutler (1994) reported successful prenatal diagnosis of
PK deficiency using 2 different techniques. In the first case, they used
PCR amplification and restriction endonuclease analysis and identified a
mutation in fetus genomic DNA from amniotic fluid cells. In the second
case, they used cord blood to analyze 2 polymorphic sites linked to the
PKRL gene and were able to identify which chromosome had been inherited
from which parent.

POPULATION GENETICS

In a scheme to detect mutational events, Satoh et al. (1983) screened
for activity in erythrocytes of 11 enzymes chosen because of relatively
small coefficients of variation for mean activity. The object was to
determine the frequency of heterozygotes as identified by activities at
or below 66% of the mean value. The frequency of heterozygotes per 1,000
persons varied, with PK being 13.8 per 1,000. For these same enzymes the
frequency of 'rare' electrophoretic variants is 2.3/1,000 in the
Japanese, almost precisely the same.

Muir et al. (1984) extended the observations on PK deficiency in the
Amish with identification of 8 affected persons in Geauga County, Ohio.
Earlier reported cases came from Mifflin County, Pennsylvania (Bowman et
al., 1965). All 8 Ohio cases were traced to a common ancestor in Mifflin
County; his sister was a common ancestor of all cases identified in the
original studies (Bowman et al., 1965). The common ancestor was
Christopher Beiler, son of Jacob Beiler (born 1772) and Ferona Beiler
and brother of Anna, wife of 'Strong' Jacob Yoder, who was the
progenitor identified by Bowman et al. (1965).

From laboratories performing tests for PK deficiency and from attending
physicians in the province of Quebec, de Medicis et al. (1992) collected
58 cases of hereditary nonspherocytic hemolytic anemia due to deficiency
of the enzyme. Using the postal addresses of the probands, a prevalence
map was constructed for the various regions of the province. The
prevalence was found to be higher in eastern Quebec (1 in 81,838) than
in western Quebec (1 in 139,086). Fifty probands were French Canadian,
whereas the remaining 6 were recent immigrants.

On the basis of gene frequency, Beutler and Gelbart (2000) estimated
that the prevalence of homozygous PK deficiency is 51 cases per million
in the white population. Carey et al. (2000) had been centrally
registering all patients with PK deficiency within the Northern Health
Region of the United Kingdom since 1974. In this mainly white
population, they found a prevalence of 3.3 per million, which is more
than an order of magnitude lower than the prevalence predicted by
Beutler and Gelbart (2000). In their registry there were very few older
patients. They postulated that a possible explanation for this was that
the advent of routine blood transfusion and neonatal exchange
transfusion did not occur until the post-World War II period. Both Carey
et al. (2000) and Beutler and Gelbart (2000) pointed out that prenatal
or neonatal mortality lowers the frequency with which the disease is
found in the population at large. Underdiagnosis is also likely. Beutler
and Gelbart (2000) noted that in their experience misdiagnosis is
common, even when PK assays are performed.

HISTORY

Blume et al. (1970) reported that intravenous administration of inosine
and adenine was effective therapy, leading to decreased hemolysis, in
some patients with PK deficiency.

*FIELD* SA
Adachi et al. (1977); Black et al. (1978); Dacha et al. (1977); De
Braekeleer (1991); Elder et al. (1981); Glader (1976); Keitt and
Bennett (1966); Kendall and Charlow (1977); Koller et al. (1979);
Oski and Bowman (1969); Rosa et al. (1981); Searcy et al. (1971);
Sprengers et al. (1978); Zurcher et al. (1965)
*FIELD* RF
1. Adachi, K.; Ghory, P. K.; Asakura, T.; Schwartz, E.: A monomeric
form of pyruvate kinase in human pyruvate kinase deficiency. Proc.
Nat. Acad. Sci. 74: 501-504, 1977.

2. Baronciani, L.; Beutler, E.: Molecular study of pyruvate kinase
deficient patients with hereditary nonspherocytic hemolytic anemia. J.
Clin. Invest. 95: 1702-1709, 1995.

3. Baronciani, L.; Beutler, E.: Prenatal diagnosis of pyruvate kinase
deficiency. Blood 84: 2354-2356, 1994.

4. Baronciani, L.; Bianchi, P.; Zanella, A.: Hematologically important
mutations: red cell pyruvate kinase. Blood Cells Molecules Dis. 22:
85-89, 1996.

5. Beutler, E.; Baronciani, L.: Mutations in pyruvate kinase. Hum.
Mutat. 7: 1-6, 1996.

6. Beutler, E.; Forman, L.; Rios-Larrain, E.: Elevated pyruvate kinase
activity in patients with hemolytic anemia due to red cell pyruvate
kinase 'deficiency.'. Am. J. Med. 83: 899-904, 1987.

7. Beutler, E.; Gelbart, T.: PK deficiency prevalence and the limitations
of a population-based survey. (Letter) Blood 96: 4005-4006, 2000.

8. Bigley, R. H.; Koler, R. D.: Liver pyruvate kinase (PK) isozymes
in a PK-deficient patient. Ann. Hum. Genet. 31: 383-388, 1968.

9. Black, J. A.; Rittenburg, M. B.; Standerfer, R. J.; Peterson, J.
S.: Hereditary persistence of fetal erythrocyte pyruvate kinase in
the Basenji dog.In: Brewer, G. J.: The Red Cell. New York: Alan
R. Liss (pub.) 1978. Pp. 275-290.

10. Blume, K. G.; Busch, D.; Hoffbauer, R. W.; Arnold, H.; Lohr, G.
W.: The polymorphism of nucleoside effect in pyruvate kinase deficiency. Humangenetik 9:
257-259, 1970.

11. Boivin, P.; Galand, C.: A mutant of human red cell pyruvate kinase
with high affinity for phosphoenolpyruvate. Enzyme 18: 37-47, 1974.

12. Bowman, H. S.; McKusick, V. A.; Dronamraju, K. R.: Pyruvate kinase
deficient hemolytic anemia in an Amish isolate. Am. J. Hum. Genet. 17:
1-8, 1965.

13. Bowman, H. S.; Procopio, F.: Hereditary non-spherocytic hemolytic
anemia of the pyruvate-kinase deficient type. Ann. Intern. Med. 58:
567-591, 1963.

14. Carey, P. J.; Chandler, J.; Hendrick, A.; Reid, M. M.; Saunders,
P. W. G.; Tinegate, H.; Taylor, P. R.; West, N.: Prevalence of pyruvate
kinase deficiency in a northern European population in the north of
England. (Letter) Blood 96: 4005 only, 2000.

15. Dacha, M.; Canestrari, F.; Bossu, M.; Rossi-Ferrini, P. L.; Fornaini,
G.: Inherited erythrocyte pyruvate kinase deficiency: studies on
15 members of two related families. Acta Haemat. 57: 37-46, 1977.

16. De Braekeleer, M.: Hereditary disorders in Saguenay-Lac-St-Jean
(Quebec, Canada). Hum. Hered. 41: 141-146, 1991.

17. de Medicis, E.; Ross, P.; Friedman, R.; Hume, H.; Marceau, D.;
Milot, M.; Lyonnais, J.; De Braekeleer, M.: Hereditary nonspherocytic
hemolytic anemia due to pyruvate kinase deficiency: a prevalence study
in Quebec (Canada). Hum. Hered. 42: 179-183, 1992.

18. Dente, L.; D'Urso, M.; Di Maio, S.; Brancaccio, V.; Luzzatto,
L.: Pyruvate kinase deficiency: characterization of two new genetic
variants. Clin. Chim. Acta 126: 143-154, 1982.

19. Elder, G. E.; Lappin, T. R. J.; Lawson, B. E.; Bridges, J. M.
: Three pyruvate kinase variants with increased affinity for PEP. Brit.
J. Haemat. 47: 371-381, 1981.

20. Etiemble, J.; Picat, C.; Boivin, P.: A red cell pyruvate kinase
mutant with normal L-type PK in the liver. Hum. Genet. 61: 256-258,
1982.

21. Etiemble, J.; Picat, C.; Dhermy, D.; Buc, H. A.; Morin, M.; Boivin,
P.: Erythrocytic pyruvate kinase deficiency and hemolytic anemia
inherited as a dominant trait. Am. J. Hemat. 17: 251-260, 1984.

22. Fermo, E.; Bianchi, P.; Chiarelli, L. R.; Cotton, F.; Vercellati,
C.; Writzl, K.; Baker, K.; Hann, I.; Rodwell, R.; Valentini, G.; Zanella,
A.: Red cell pyruvate kinase deficiency: 17 new mutations of the
PK-LR gene. Brit. J. Haemat. 129: 839-846, 2005. Note: Erratum:
Brit. J. Haemat. 130: 973 only, 2005.

23. Gilsanz, F.; Vega, M. A.; Gomez-Castillo, E.; Ruiz-Balda, J. A.;
Omenaca, F.: Fetal anaemia due to pyruvate kinase deficiency. Arch.
Dis. Child. 69: 523-524, 1993.

24. Ginter, D. N.: Pyruvate kinase deficiency with carotid artery
thromboses. Birth Defects Orig. Art. Ser. X(4): 305-306, 1974.

25. Glader, B. E.: Salicylate-induced injury of pyruvate-kinase-deficiency
erythrocytes. New Eng. J. Med. 294: 916-918, 1976.

26. International Committee for Standardization in Haematology:
Recommended methods for the characterization of red cell pyruvate
kinase variants. Brit. J. Haemat. 43: 275-286, 1979.

27. Kahn, A.; Marie, J.; Vives-Corrons, J. L.; Maigret, P.; Najman,
A.: Search for a relationship between molecular anomalies of the
mutant erythrocyte pyruvate kinase variants and their pathological
expression. Hum. Genet. 57: 172-175, 1981.

28. Kanno, H.; Fujii, H.; Hirono, A.; Miwa, S.: cDNA cloning of human
R-type pyruvate kinase and identification of a single amino acid substitution
(thr384-to-met) affecting enzymatic stability in a pyruvate kinase
variant (PK Tokyo) associated with hereditary hemolytic anemia. Proc.
Nat. Acad. Sci. 88: 8218-8221, 1991.

29. Keitt, A. S.; Bennett, D. C.: Pyruvate kinase deficiency and
related disorders of red cell glycolysis. Am. J. Med. 41: 762-785,
1966.

30. Kendall, A. G.; Charlow, G. F.: Red cell pyruvate kinase deficiency:
adverse effect of oral contraceptives. Acta Haemat. 57: 116-120,
1977.

31. Koler, R. D.; Bigley, R. H.; Jones, R. T.; Rigas, D. A.; Vanbellinghen,
P.; Thompson, P.: Pyruvate kinase: molecular differences between
human red cell and leukocyte enzymes. Cold Spring Harbor Symp. Quant.
Biol. 24: 213-221, 1964.

32. Koller, C. A.; Orringer, E. P.; Parker, J. C.: Quinine protects
pyruvate-kinase deficient red cells from dehydration. Am. J. Hemat. 7:
193-199, 1979.

33. Lakomek, M.; Tillmann, W.; Scharnetzky, M.; Schroter, W.; Winkler,
H.: Erythrocyte pyruvate kinase deficiency: a kinetic study of the
membrane-localised and cytoplasmatic enzyme from six patients. Enzyme 29:
189-197, 1983.

34. Larochelle, A.; De Braekeleer, M.; Marceau, D.; de Medicis, E.
: Hereditary non-spherocytic hemolytic anemia: a pyruvate kinase mutation
in Quebec patients. Miami Short Reports. Advances in Gene Technology
: The Molecular Biology of Human Genetic Disease. Vol. 1 New York:
IRL Press (pub.) 1991. P. 33.

35. Miwa, S.; Fujii, H.: Molecular basis of erythroenzymopathies
associated with hereditary hemolytic anemia: tabulation of mutant
enzymes. Am. J. Hemat. 51: 122-132, 1996.

36. Muir, W. A.; Beutler, E.; Wasson, C.: Erythrocyte pyruvate kinase
deficiency in the Ohio Amish: origin and characterization of the mutant
enzyme. Am. J. Hum. Genet. 36: 634-639, 1984.

37. Necheles, T. F.; Finkel, H. E.; Sheehan, R. G.; Allen, D. M.:
Red cell pyruvate kinase deficiency. The effect of splenectomy. Arch.
Intern. Med. 118: 75-78, 1966.

38. Oski, F. A.; Bowman, H.: A low k(m) phosphoenolpyruvate mutant
in the Amish with red cell pyruvate kinase deficiency. Brit. J. Haemat. 17:
289-297, 1969.

39. Paglia, D. E.; Keitt, A. S.; Valentine, W. N.; Gordon, S.: Biochemical
characterization of three mutant isozymes of erythrocyte pyruvate
kinase: PK-'Gainesville,' PK-'San Juan,' and PK-'Cape Canaveral'. Am.
J. Hemat. 14: 335-344, 1983.

40. Paglia, D. E.; Valentine, W. N.; Baughan, M. A.; Miller, D. R.;
Reed, C. F.; McIntyre, O. R.: An inherited molecular lesion of erythrocyte
pyruvate kinase. Identification of a kinetically aberrant isozyme
associated with premature hemolysis. J. Clin. Invest. 47: 1929-1946,
1968.

41. Paglia, D. E.; Valentine, W. N.; Holbrook, C. T.; Brockway, R.
: Pyruvate kinase isozyme (PK-Greenville) with defective allosteric
activation by fructose-1,6-diphosphate: the role of F-1,6-P modulation
in normal erythrocyte metabolism. Blood 62: 972-979, 1983.

42. Pissard, S.; Max-Audit, I.; Skopinski, L.; Vasson, A.; Vivien,
P.; Bimet, C.; Goossens, M.; Galacteros, F.; Wajcman, H.: Pyruvate
kinase deficiency in France: a 3-year study reveals 27 new mutations. Brit.
J. Haemat. 133: 683-689, 2006.

43. Rosa, R.; Max-Audit, I.; Izrael, V.; Beuzard, Y.; Thillet, J.;
Rosa, J.: Hereditary pyruvate kinase abnormalities associated with
erythrocytosis. Am. J. Hemat. 10: 47-55, 1981.

44. Rouger, H.; Valentin, C.; Craescu, C. T.; Galacteros, F.; Cohen-Solal,
M.: Five unknown mutations in the LR pyruvate kinase gene associated
with severe hereditary nonspherocytic haemolytic anaemia in France. Brit.
J. Haemat. 92: 825-830, 1996.

45. Sachs, J. R.; Wicker, D. J.; Gilcher, R. O.; Conrad, M. E.; Cohen,
R. J.: Familial hemolytic anemia resulting from an abnormal red blood
cell pyruvate kinase. J. Lab. Clin. Med. 72: 359-362, 1968.

46. Satoh, C.; Neel, J. V.; Yamashita, A.; Goriki, K.; Fujita, M.;
Hamilton, H. B.: The frequency among Japanese of heterozygotes for
deficiency variants of 11 enzymes. Am. J. Hum. Genet. 35: 656-674,
1983.

47. Schroter, W.; Lakomek, M.; Scharnetzky, M.; Tillmann, W.; Winkler,
H.: Pyruvate kinase 'Gottingen-1,2': congenital hemolytic anemia,
evidence of double heterozygosity, and lack of enzyme cooperativity. Hum.
Genet. 60: 381-386, 1982.

48. Searcy, G. P.; Miller, D. R.; Tasker, J. B.: Congenital hemolytic
anemia in the Basenji dog due to erythrocyte pyruvate kinase deficiency. Canad.
J. Comp. Med. 35: 67-70, 1971.

49. Shinohara, K.; Miwa, S.; Nakashima, K.; Oda, E.; Kageoka, T.;
Tsujino, G.: A new pyruvate kinase variant (PK Osaka) demonstrated
by partial purification and condensation. Am. J. Hum. Genet. 28:
474-481, 1976.

50. Sprengers, E. D.; Beemer, F. A.; Staal, G. E. J.: A new pyruvate
kinase variant: PK-Wouw. J. Molec. Med. 3: 271-278, 1978.

51. Tanaka, K. R.; Valentine, W. N.; Miwa, S.: Pyruvate kinase (PK)
deficiency hereditary nonspherocytic hemolytic anemia. Blood 19:
267-295, 1962.

52. Tani, K.; Fujii, H.; Nagata, S.; Miwa, S.: Human liver type pyruvate
kinase: complete amino acid sequence and the expression in mammalian
cells. Proc. Nat. Acad. Sci. 85: 1792-1795, 1988.

53. Valentine, W. N.; Herring, W. B.; Paglia, D. E.; Steuterman, M.
C.; Brockway, R. A.; Nakatani, M.: Pyruvate kinase Greensboro: a
four-generation study of a high K(0.5s) (phosphoenoylpyruvate) variant. Blood 72:
1054-1059, 1988. Note: Erratum: Blood 72: 2082 only, 1988.

54. Valentine, W. N.; Tanaka, K. R.; Miwa, S.: A specific erythrocyte
glycolytic enzyme defect (pyruvate kinase) in three subjects with
congenital non-spherocytic hemolytic anemia. Trans. Assoc. Am. Physicians 74:
100-110, 1961.

55. Vives-Corrons, J. L.; Marie, J.; Pujades, M. A.; Kahn, A.: Hereditary
erythrocyte pyruvate-kinase (PK) deficiency and chronic hemolytic
anemia: clinical, genetic and molecular studies in six new Spanish
patients. Hum. Genet. 53: 401-408, 1980.

56. Zanella, A.; Fermo, E.; Bianchi, P.; Valentini, G.: Red cell
pyruvate kinase deficiency: molecular and clinical aspects. Brit.
J. Haemat. 130: 11-25, 2005.

57. Zanella, A.; Robulla, P.; Vullo, C.; Izzo, C.; Tedesco, F.; Sirchia,
G.: Hereditary pyruvate kinase deficiency: role of the abnormal enzyme
in red cell pathophysiology. Brit. J. Haemat. 40: 551-562, 1978.

58. Zuelzer, W. W.; Robinson, A. R.; Hsu, T. H. J.: Erythrocyte pyruvate
kinase deficiency in non-spherocytic hemolytic anemia: a system of
multiple genetic markers? Blood 32: 33-48, 1968.

59. Zurcher, C.; Loos, J. A.; Prins, H. K.: Hereditary high ATP content
of human erythrocytes. Bibl. Haematol. 23: 549-556, 1965.

*FIELD* CS
INHERITANCE:
Autosomal recessive

GROWTH:
[Other];
Intrauterine growth retardation, IUGR (rare)

ABDOMEN:
[Liver];
Jaundice;
[Biliary tract];
Cholelithiasis;
Cholecystitis;
[Spleen];
Splenomegaly

SKIN, NAILS, HAIR:
[Skin];
Jaundice (sometimes onset in the neonatal period)

HEMATOLOGY:
Hemolytic anemia, chronic;
Severity of anemia can range from mild to life-threatening;
Anemia may be exacerbated during infection or pregnancy;
Increased red cell osmotic fragility

PRENATAL MANIFESTATIONS:
[Amniotic fluid];
Hydrops fetalis, non-immune (rare)

LABORATORY ABNORMALITIES:
Decreased hemoglobin;
Increased reticulocytes;
Increased unconjugated bilirubin;
Decreased red cell pyruvate kinase activity

MISCELLANEOUS:
Onset in infancy, but may not be diagnosed until later in mild cases;
Variably severity;
Rare patients with homozygous null mutations have most severe disease

MOLECULAR BASIS:
Caused by mutations in the red cell pyruvate kinase gene (PKRL, 609712.0001).

*FIELD* CN
Cassandra L. Kniffin - revised: 11/16/2005

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 09/13/2006
ckniffin: 11/16/2005

*FIELD* CN
Cassandra L. Kniffin - updated: 9/5/2006
Cassandra L. Kniffin - reorganized: 11/18/2005
Cassandra L. Kniffin - updated: 11/16/2005
Victor A. McKusick - updated: 1/11/2005
Victor A. McKusick - updated: 12/2/2003
Victor A. McKusick - updated: 5/19/2003
Victor A. McKusick - updated: 8/13/2002
Victor A. McKusick - updated: 2/26/2002
Victor A. McKusick - updated: 6/26/2001
Victor A. McKusick - updated: 2/15/2001
Victor A. McKusick - updated: 3/24/1999
Victor A. McKusick - updated: 1/27/1999
Victor A. McKusick - updated: 11/10/1998
Victor A. McKusick - updated: 7/28/1998
Victor A. McKusick - updated: 8/7/1997
Victor A. McKusick - updated: 6/21/1997
Victor A. McKusick - updated: 5/15/1997
Mark H. Paalman - updated: 4/17/1997

*FIELD* CD
Victor A. McKusick: 6/24/1986

*FIELD* ED
carol: 04/19/2013
terry: 8/17/2012
carol: 9/14/2009
wwang: 10/2/2006
ckniffin: 9/5/2006
carol: 11/18/2005
ckniffin: 11/16/2005
tkritzer: 1/21/2005
terry: 1/11/2005
carol: 3/17/2004
alopez: 12/2/2003
terry: 12/2/2003
carol: 6/3/2003
tkritzer: 5/29/2003
terry: 5/20/2003
tkritzer: 5/19/2003
tkritzer: 8/19/2002
terry: 8/13/2002
mgross: 3/6/2002
terry: 2/26/2002
carol: 11/29/2001
mcapotos: 7/2/2001
terry: 6/26/2001
carol: 2/26/2001
cwells: 2/21/2001
terry: 2/15/2001
terry: 3/24/1999
carol: 2/12/1999
terry: 1/27/1999
carol: 11/17/1998
terry: 11/16/1998
terry: 11/10/1998
carol: 7/29/1998
terry: 7/28/1998
terry: 7/24/1998
terry: 8/11/1997
terry: 8/7/1997
terry: 6/24/1997
terry: 6/21/1997
mark: 5/15/1997
alopez: 5/8/1997
mark: 4/17/1997
jenny: 3/31/1997
terry: 11/12/1996
terry: 11/4/1996
carol: 8/22/1996
marlene: 8/2/1996
terry: 7/26/1996
mark: 3/30/1996
terry: 3/21/1996
mark: 3/7/1996
mark: 1/30/1996
mark: 1/24/1996
mark: 1/22/1996
joanna: 1/17/1996
joanna: 1/15/1996
mark: 5/5/1995
carol: 2/1/1995
davew: 8/31/1994
pfoster: 4/25/1994
warfield: 4/19/1994
mimadm: 4/12/1994

MIM 609712
*RECORD*
*FIELD* NO
609712
*FIELD* TI
*609712 PYRUVATE KINASE, LIVER AND RED BLOOD CELL; PKLR
;;PKRL;;
PYRUVATE KINASE, LIVER TYPE; PKL;;
read morePYRUVATE KINASE, RED CELL TYPE; PKR;;
PYRUVATE KINASE 1; PK1
*FIELD* TX

DESCRIPTION

The PKLR gene encodes pyruvate kinase (EC 2.7.1.40), a glycolytic enzyme
that catalyzes the transphosphorylation from phosphoenolpyruvate (PEP)
to ADP, yielding pyruvate and ATP. It is the last step of the glycolytic
pathway and is essentially irreversible.

The PKLR gene codes for both the liver and red blood cell isozymes. The
PKM2 gene (179050), located on chromosome 15q22, encodes 2
muscle-specific isoforms, M1 and M2 (Zanella et al., 2005).

CLONING

Tani et al. (1987, 1988) isolated a cDNA corresponding to the human
liver pyruvate kinase gene from a Japanese adult human liver cDNA
library using a rat liver-type PK cDNA probe. The deduced 543-amino acid
protein has a calculated molecular mass of 58.6 kD and shows 92.4%
similarity to the rat protein. The PK enzyme functions as a
homotetramer. Studies with the rat enzyme suggested that the red cell
type is longer than the liver type in the 5-prime terminal end, but the
rest of the sequence is very similar. Kanno et al. (1991) isolated a
cDNA clone corresponding to the human red blood cell PK gene from a
human reticulocyte cDNA library. The deduced protein sequence was
similar to that of L-type PK, with an additional 31 amino acids at the N
terminus. Tani et al. (1987) cited kinetic, electrophoretic, and
immunologic evidence that the liver and red cell types of PK differ from
the M1 and M2 types, and that these 2 classes of isozymes are probably
under the control of different genes. They also cited studies with the
rat PK genes suggesting that the M1 and M2 types of PK on the one hand,
and the liver and red cell types on the other, are coded by separate
structural genes and are translated from individual mRNAs.

Bigley and Koler (1968), Shinohara et al. (1976), and Nakashima et al.
(1977) presented strong genetic evidence that the L- and R-type PK
enzymes are encoded by the same structural gene.

By studies of in vitro protein synthesis using RNA extracted from rat
red cells and liver, Marie et al. (1981) demonstrated that the
difference between the L- and R-type pyruvate kinases is due to
tissue-specific mRNAs, likely resulting from differential processing of
a common nuclear RNA precursor. The work was repeated using fetal human
liver with identical results.

Lacronique et al. (1992) showed both in vitro and in vivo that the rat
R- and L-specific PK enzymes are produced from different transcription
units operating with 2 cell-restricted promoters which, due to
protein-DNA interactions, are mutually exclusive.

MAPPING

By a combination of somatic cell hybrid studies and in situ
hybridization, Tani et al. (1987) and Satoh et al. (1988) mapped the
PKLR gene to chromosome 1q21-q22.

Glenn et al. (1994) found that 2 polymorphisms, one in the PKLR gene and
one in the glucocerebrosidase gene (GBA; 606463), both of which are
located in band 1q21, are tightly linked. Each of 3 Gaucher disease
(230800) mutations in 112 chromosomes studied was associated with a
unique haplotype. With a conservative assumption about the length of
time that the Gaucher disease mutation has been present in the Jewish
population, Glenn et al. (1994) deduced that the genetic distance
between these 2 loci is probably less than 0.2 cM. These polymorphic
loci produced 4 haplotypes, but 2 of these are relatively uncommon
because the polymorphic sites are in linkage disequilibrium. The markers
are potentially useful in the prenatal diagnosis of pyruvate kinase
deficiency in families that have at least 1 affected child and may also
be helpful in heterozygote detection in families with Gaucher disease in
which a specific mutation producing the disease is unknown. Close
linkage of the PKLR and GBA genes was also demonstrated by Rockah et al.
(1998), who found linkage disequilibrium between the 2 common Ashkenazi
Jewish mutations and polymorphisms in the PKLR gene. One hundred of 104
(96%) alleles carrying the 1226G mutation (606463.0003) also carried the
A1 allele of the PKLR gene, which was present in only 6.7% of the
control population. The calculated linkage disequilibrium between 1226G
and the A1 allele was 0.957. Mutation 84GG (606463.0014) of the GBA gene
was found to be associated uniquely with the PKLR A6 allele, with a
linkage disequilibrium of 1.00.

Mateu et al. (2002) found complete linkage disequilibrium in the
PKLR-GBA region over 70 kb in a set of worldwide populations. Variation
at PKLR-GBA was also tightly linked to that at the GBA pseudogene, 16 kb
downstream from GBA. Thus, a 90-kb linkage disequilibrium block was
observed, which points to a low recombination rate in this region.

GENE FUNCTION

- Crystal Structure

Valentini et al. (2002) reported the 3-dimensional crystal structure of
human erythrocyte PK in complex with fructose 1,6-bisphosphate, the
allosteric activator, and phosphoglycolate, a PEP substrate analog. PK
is a tetramer with 4 identical subunits, each consisting of 4 domains: a
small N-terminal helical domain, which is absent in bacterial PK; an A
domain with beta-alpha barrel topology; a B domain, inserted into the A
domain; and a C domain with an alpha + beta topology. The multidomain
architecture is instrumental to the regulation of PK activity. Enzyme
activation is thought to involve a combination of domain and subunit
rotations coupled to alterations in the active site geometry. Valentini
et al. (2002) characterized 8 PK mutations, including T384M
(609712.0004), R479H (609712.0006), and R486W (609712.0009), and
concluded that mutations can target distinct regions of the protein,
including domain interfaces and catalytic and allosteric sites, which
have variable effects on enzyme thermostability, efficiency, and
regulatory properties.

MOLECULAR GENETICS

In 2 Japanese patients, born of consanguineous parents, with hereditary
hemolytic anemia due to pyruvate kinase deficiency (266200), Kanno et
al. (1991) identified a homozygous mutation in the PKLR gene
(609712.0004). Larochelle et al. (1991) identified a mutation in the
PKLR gene (609712.0001) in French Canadian patients with pyruvate kinase
deficiency.

Baronciani and Beutler (1995) found 19 different mutations among 58 of
60 PKLR alleles in 30 unrelated patients with hereditary nonspherocytic
hemolytic anemia due to PK deficiency. Miwa and Fujii (1996) tabulated
47 mutations in the PK gene known to result in hereditary hemolytic
anemia. Rouger et al. (1996) identified 7 different PK mutations in 26
unrelated families in France; 5 of these had not previously been
described. Beutler and Baronciani (1996) found that in all 55 different
mutations that had been described in patients with PK-deficient
hemolytic anemia, the mutations were widely distributed, occurring
throughout exons 4 to 12 in this 12-exon gene. Baronciani et al. (1996)
tabulated 59 different mutations in red cell pyruvate kinase of
hematologic importance.

Zanella et al. (1997) found 26 mutated alleles among 15 Italian patients
with PK deficiency; these included 14 different alleles, 8 of which had
not previously been described. Zanella et al. (2001) studied 16
unrelated patients with congenital hemolytic anemia associated with
erythrocyte PK deficiency and found 15 different mutations among the 28
mutated alleles identified. Eight of these were novel. The most frequent
mutation in Italy appeared to be 1456C-T (609712.0009).

Lenzner et al. (1997) studied the PKLR gene in 29 unrelated patients
from Central Europe with hereditary nonspherocytic hemolytic anemia due
to PK deficiency. Among 58 potentially affected alleles, 53 mutations
were identified, of which 17 were different and 6 were described for the
first time.

Demina et al. (1998) described 6 PKLR mutations associated with enzyme
deficiency. The mutations were from 7 unrelated subjects, of whom 5 had
hemolytic anemia. They reviewed previously described mutations and
concluded that there were not sufficient data to draw conclusions
regarding genotype/phenotype relationship.

In 12 unrelated Spanish patients with red cell PK deficiency and
hereditary nonspherocytic hemolytic anemia, Zarza et al. (1998) found a
total of 10 different mutations in 22 of 24 chromosomes. Eight of these
were missense mutations and 2 were nonsense mutations. The same mutation
(609712.0009) was identified in 7 of 22 alleles. Six of the mutations
had not previously been described. No cases of the 1529G-A mutation
(609712.0007), common in northern European populations, were found in
Spain.

In 23 patients from 21 unrelated families with PK deficiency, Fermo et
al. (2005) identified a total of 27 different mutations in the PKLR
gene, including 17 novel mutations. In a detailed review of PK
deficiency, Zanella et al. (2005) stated that more than 150 different
PKLR mutations had been identified.

Pissard et al. (2006) identified 41 different mutations in the PKLR
gene, including 27 novel mutations, among 56 French families with PK
deficiency. Most cases were ascertained because of neonatal or chronic
anemia; 2 cases were lethal in the neonatal period.

In 18 unrelated Indian patients with PK deficiency, Kedar et al. (2009)
identified 17 different mutations, including 10 novel mutations, in the
PKLR gene.

- Pyruvate Kinase Deficiency and Malaria

Ayi et al. (2008) studied invasion and phagocytosis of Plasmodium
falciparum, the causative agent of malaria (see 611162), in patients of
Italian and French ancestry with PK deficiency. They found that
macrophages from patients homozygous for a 1269G-A mutation
(609712.0013) or a 1-bp deletion of 823G (609712.0014) in PKLR showed
reduced parasite invasion of erythrocytes and increased
complement-mediated parasite phagocytosis compared with macrophages from
asymptomatic relatives heterozygous for 1269G-A and wildtype controls.
HapMap analysis of various populations, including those from
malaria-endemic areas, failed to detect PKLR SNP differences. Ayi et al.
(2008) proposed that heterozygosity for loss-of-function PKLR alleles,
but probably not homozygosity due to the poor overall health status of
anemic PK-deficient patients, may provide modest but significant
protection against malaria, leading to retention of mutant alleles in
malaria-endemic regions.

GENOTYPE/PHENOTYPE CORRELATIONS

Boo Sedano et al. (2004) reported a large Swiss kindred with complex
consanguinity and pyruvate kinase deficiency, designated PK Aarau. In 4
affected members, they identified a homozygous nonsense mutation in the
PK gene (609712.0012). The phenotype was especially severe: 12 family
members were diagnosed as the result of life-threatening neonatal anemia
and jaundice. Five died within 2 days of birth; all 7 surviving
individuals required multiple blood transfusions and were splenectomized
later in childhood. One patient died at the age of 11 years because of
septicemia after splenectomy.

ANIMAL MODEL

Morimoto et al. (1995) described the characteristics of mutant mice with
splenomegaly and nonspherocytic hemolytic anemia due to deficiency of
red blood cell pyruvate kinase. The locus in the mouse was situated on
chromosome 3.

In humans, initial susceptibility to infection with Plasmodium species,
disease severity, and ultimate outcome of malaria (self-healing or
lethal) are under complex genetic control (see 611162). Alleles
associated with sickle cell anemia (603903), beta-thalassemia (613985),
and G6PD deficiency (300908) have a protective effect against malaria
and may have been retained by positive selection in areas of endemic
malaria. Genetic variations in erythrocyte antigens, including Duffy
(DARC; 613665) and Gerbich (110750), and levels of host cytokines affect
type and severity of malaria. Min-Oo et al. (2003) used a mouse model of
infection with Plasmodium chabaudi to study the genetic component of
malaria susceptibility. They found that 2 recombinant congenic strains
were unusually resistant to malaria. Malaria resistance was associated
with splenomegaly and constitutive reticulocytosis, was inherited in an
autosomal recessive fashion, and was controlled by a locus on chromosome
3, which they designated Char4. Sequencing of candidate genes from the
Char4 region identified a loss-of-function mutation (269T-A, resulting
in the amino acid substitution I90N) in the PK gene as underlying the
malaria resistance in these strains. These results suggested that
pyruvate kinase deficiency may be similarly protective against malaria
in humans.

*FIELD* AV
.0001
PYRUVATE KINASE DEFICIENCY
PKLR, 1-BP DEL

In French Canadian patients with pyruvate kinase deficiency (266200),
Larochelle et al. (1991) identified a 1-bp deletion at position 69 in
exon 6 of the PKLR gene. The frameshift mutation resulted in the
appearance of a stop codon located in the region of the active catalytic
site of the enzyme. De Braekeleer (1991) estimated the prevalence at
birth of PK deficiency to be 1/16,490 in the French Canadian population
of the Saguenay-Lac-Saint-Jean region of Quebec province.

.0002
PYRUVATE KINASE DEFICIENCY
PKLR, ARG132CYS

In a boy of Turkish origin born in Linz, Austria, with pyruvate kinase
deficiency (266200), Neubauer et al. (1991) identified a homozygous
394C-T transition in the PKLR gene, resulting in an arg132-to-cys
(R132C) substitution. Before splenectomy at the age of 26 months, the
patient had required 26 RBC transfusions; in the following 2 years, only
2 transfusions were required. The patient's parents were first cousins.
The mutant enzyme showed markedly reduced specific activity and
thermolability.

.0003
PYRUVATE KINASE DEFICIENCY
PKLR, THR353MET

In a boy born in Beirut with pyruvate kinase deficiency (266200),
Neubauer et al. (1991) identified a homozygous 1058T-C transition in the
PKLR gene, resulting in a thr353-to-met (T353M) substitution. The amino
acid change lies outside the deduced substrate binding site, and the
kinetic parameters of PK Beirut were close to normal. The patient was
jaundiced for almost the first 2 years of life but did not receive a
transfusion until the age of 8; only 3 RBC transfusions had been given
before age 12. The patient's parents were first cousins.

.0004
PYRUVATE KINASE DEFICIENCY
PKLR, THR384MET

In 2 Japanese patients, born of consanguineous parents, with hereditary
hemolytic anemia due to PK Tokyo (266200), Kanno et al. (1991)
identified a homozygous 1151C-T transition in the PKLR gene, resulting
in a thr384-to-met (T384M) substitution in a highly conserved residue at
the end of the seventh alpha-helix of the A domain. Functional
expression studies showed that the mutant enzyme had decreased
stability. Each parent was heterozygous for the mutation.

.0005
PYRUVATE KINASE DEFICIENCY
PKLR, GLN421LYS

In 2 Japanese patients with PK deficiency (266200), known as PK
Fukushima and PK Maebashi, Kanno et al. (1992) identified a 1261C-A
transversion in the PKLR gene, resulting in a gln421-to-lys (Q421K)
substitution. The authors also found a common polymorphic change, a
1705A-C transversion resulting in a silent mutation.

.0006
PYRUVATE KINASE DEFICIENCY, AMISH TYPE
PKLR, ARG479HIS

In the form of pyruvate kinase deficiency (266200) observed among the
Old Order Amish of Pennsylvania by Bowman and Procopio (1963) and Bowman
et al. (1965), Kanno et al. (1994) identified a 1436G-A transition in
the PKLR gene, resulting in an arg479-to-his (R479H) substitution.

Valentini et al. (2002) demonstrated that although the R479H
substitution occurs in the allosteric site of the PK enzyme, it does not
interfere with kinetic parameters. They observed that the 1436G-A change
may affect a splicing site at the 3-prime end of exon 10, resulting in
abnormal splicing.

Kedar et al. (2009) identified the R479H mutation in 7 (19.4%) of 36
alleles in 18 Indian patients with PK deficiency.

.0007
PYRUVATE KINASE DEFICIENCY
PKLR, ARG510GLN

Baronciani and Beutler (1995) identified a 1529G-A transition in the
PKLR gene, resulting in an arg510-to-gln (R510Q) substitution, as the
most common mutation causing pyruvate kinase deficiency (266200) in
Europeans. The authors found this mutation in 25 of 58 alleles that
could be characterized in 30 unrelated patients with hereditary
nonspherocytic hemolytic anemia with deficiency of pyruvate kinase by
enzyme assay. With a single exception, this mutation was in linkage
disequilibrium with 2 polymorphic markers, i.e., it was found with 1705C
for the 1705A/C polymorphism and with 14 repeats in a microsatellite in
intron 11. This finding was considered to be consistent with a single
origin of this common mutation.

Lenzner et al. (1997) found the 1529G-A mutation in 24 of 58 mutated
alleles (45.3%) in 29 unrelated patients with PK deficiency in Central
Europe. Nine patients were homozygous for the mutation; 6 were compound
heterozygotes. They found that the mutation was more frequent among
patients of German and English origin (14 of 18 patients were either
homozygous or heterozygous) than among patients from Czechia/Slovakia (1
homozygote among 11 patients). Other mutations were found exclusively in
the Czechia/Slovakia group and never among German and English patients.
Nine patients homozygous for the 1529G-A mutation showed the same
haplotype for 4 markers. However, the hematologic and clinical findings
in these patients were different. Clinical symptoms ranged from a mild
compensated hemolysis to intermediate anemia and severe anemia. All
showed low residual enzyme activity between approximately 10 and 25% of
normal, of which the more severe cases had lower PK activities than the
milder forms. Reticulocyte counts varied between approximately 5 and 8%
in the slightly affected patients to 25 to 66% in the seriously affected
patients. The severely affected patients were characterized by a
compensatory persistence of the M2-type enzyme in red cells, which
accounted for about half of the residual PK activity.

Wang et al. (2001) studied the mutant R510Q protein. Functional
expression studies showed that the mutant protein retained its binding
capacity to, and could be activated by, fructose 1,6-bisphosphate, and
showed similar kinetics toward phosphoenolpyruvate and adenosine
diphosphate as the wildtype enzyme. Conversely, the mutant protein had a
dramatically decreased stability toward heat and was more susceptible to
ATP inhibition.

.0008
ADENOSINE TRIPHOSPHATE, ELEVATED, OF ERYTHROCYTES
PKLR, GLY37GLN

Beutler et al. (1997) restudied the Dutch family with hereditary
elevation of red cell ATP levels reported by Zurcher et al. (1965) and
identified a 110G-A transition in the PKLR gene, resulting in a
gly37-to-glu (G37E) substitution. In the title of the article, the
mutation is referred to as 'G-to-T' and the substitution as 'K37Q,' but
Beutler (1997) confirmed the mutation as a 110G-A transition resulting
in a glycine-to-glutamic acid change at residue 37 (G37E). The mutation
was present in heterozygous state. Beutler et al. (1997) stated it is
possible that different mutations in the PKLR gene are responsible for
the finding in other families with elevated red cell ATP levels
(102900), because the enzyme kinetics in other families have been
different from those in the family reported by Zurcher et al. (1965).

.0009
PYRUVATE KINASE DEFICIENCY
PKLR, ARG486TRP

Zarza et al. (1998) found that the most frequent mutation of the PKLR
gene causing pyruvate kinase deficiency (266200) and hereditary
nonspherocytic hemolytic anemia in Spain is a 1456C-T transition,
resulting in an arg486-to-trp (R486W) substitution. The mutation was
identified in approximately one-third of mutant alleles (7 of 22).

Zanella et al. (2001) found that the R486W mutation appeared to be the
most frequent mutation causing hemolytic anemia associated with PK
deficiency in Italy.

Kedar et al. (2009) identified the R486W mutation in 6 (16.7%) of 36
alleles in 18 Indian patients with PK deficiency.

.0010
PYRUVATE KINASE DEFICIENCY
PKLR, SER130TYR

Cohen-Solal et al. (1998) reported a Guinean woman with episodes of
marked anemia, repeated typical metaphyseal painful crises,
hemosiderosis, and pyruvate kinase deficiency (266200). Sequencing of
the PKLR gene revealed a 2670C-A transversion in exon 5 of the PKLR
gene, resulting in a ser130-to-tyr (S130Y) substitution, which the
authors referred to as 'PK Conakry.' In addition, the patient carried a
hemoglobin S variant, L80V (141850.0035), referred to as 'Hb Conakry,'
which seemed to have a mild effect. The PK deficiency resulted in a high
intraerythrocytic 2,3-DPG concentration and a decreased oxygen affinity
which favored sickling to a level similar to that of S/C compound
heterozygous patients.

.0011
PYRUVATE KINASE DEFICIENCY
PKLR, -83G-C

In a white male patient with severe nonspherocytic hemolytic anemia, van
Wijk et al. (2003) determined the molecular basis for pyruvate kinase
deficiency (266200). On the paternal allele of the PKLR gene, they
identified the common 1529G-A mutation (609712.0007); on the maternal
allele they identified 3 in cis mutations in the erythroid-specific
promoter region: -83G-C, -324T-A, and -248delT. Analysis of the
patient's RNA demonstrated the presence of only the 1529A allele,
indicating severely reduced transcription from the allele linked to the
mutated promoter region. Transfection of promoter constructs into
erythroleukemic K562 cells showed that the -83G-C mutation strongly
reduced promoter activity and that the other 2 mutations were
nonfunctional. Site-directed mutagenesis of the promoter region revealed
the presence of a putative regulatory element (PKR-RE1) whose core
binding motif, CTCTG, is located between nucleotides -87 and -83. Van
Wijk et al. (2003) performed further studies that indicated binding of
an unidentified trans-acting factor that mediates the effects of factors
necessary for regulation of pyruvate kinase gene expression during red
cell differentiation and maturation.

.0012
PYRUVATE KINASE DEFICIENCY
PKLR, 1318G-T

In 4 affected members of a large Swiss kindred with complex
consanguinity with pyruvate kinase deficiency (266200), designated PK
Aarau, Boo Sedano et al. (2004) identified a homozygous 1318G-T
transversion in the PKLR gene, resulting in a premature termination of
translation and a truncated protein lacking a terminal fragment of 33
amino acids. Twelve members of the family were diagnosed as the result
of life-threatening neonatal anemia and jaundice. Five died within 2
days of birth; all 7 surviving individuals required multiple blood
transfusions and were splenectomized later in childhood. One patient
died at the age of 11 years because of septicemia after splenectomy.

.0013
PYRUVATE KINASE DEFICIENCY
PKLR, 1269G-A

Ayi et al. (2008) reported 2 Canadian patients of Italian ancestry with
PK deficiency (266200) who presented with nonspherocytic anemia and were
homozygous for an A-to-G mutation at position 1269 at the 3-prime end of
exon 9 of the PKLR gene, leading to a splicing defect and loss of
function. Both patients had undergone splenectomy. Heterozygous
relatives were asymptomatic and had normal hemoglobin values. Ayi et al.
(2008) found that homozygosity for the 1269G-A mutation resulted in in
vitro protection of erythrocytes from P. falciparum invasion (see
611162) and enhanced phagocytosis of parasite-infected red cells.

.0014
PYRUVATE KINASE DEFICIENCY
PKLR, 1-BP DEL, 823G

Ayi et al. (2008) reported a Canadian patient of French ancestry with PK
deficiency (266200) who presented with nonspherocytic anemia and was
homozygous for a deletion of G at position 823 in the PKLR gene, leading
to a frameshift and loss of function. The PK deficiency in this patient
was severe, and she was transfusion dependent. Ayi et al. (2008) found
that homozygosity for this mutation resulted in in vitro protection of
erythrocytes from P. falciparum invasion (see 611162), as well as
enhanced phagocytosis of parasite-infected red cells.

*FIELD* SA
Adachi et al. (1977); Beutler et al. (1987); Beutler and Gelbart (2000);
Takegawa et al. (1983); Tani et al. (1988); Tani et al. (1987); Zanella
et al. (1978)
*FIELD* RF
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*FIELD* CN
Cassandra L. Kniffin - updated: 3/4/2009
Paul J. Converse - updated: 5/27/2008
Cassandra L. Kniffin - updated: 9/5/2006

*FIELD* CD
Cassandra L. Kniffin: 11/14/2005

*FIELD* ED
carol: 10/24/2013
terry: 8/17/2012
terry: 10/26/2011
terry: 5/20/2011
mgross: 12/21/2010
terry: 5/11/2010
wwang: 3/16/2009
ckniffin: 3/4/2009
mgross: 7/10/2008
terry: 5/27/2008
mgross: 7/5/2007
wwang: 10/2/2006
ckniffin: 9/5/2006
carol: 11/18/2005
ckniffin: 11/16/2005