Blood Reviews
Volume 21, Issue 4 , Pages 217-231 , July 2007

Pyruvate kinase deficiency: The genotype-phenotype association

  • Alberto Zanella

      Affiliations

    • Department of Haematology, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy
    • Corresponding Author InformationCorresponding author. Tel.: +39 02 55033426; fax: +39 02 55033439.
    • ,
  • Elisa Fermo

      Affiliations

    • Department of Haematology, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy
    • ,
  • Paola Bianchi

      Affiliations

    • Department of Haematology, Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy
    • ,
  • Laurent Roberto Chiarelli

      Affiliations

    • Department of Genetics and Microbiology, University of Pavia, Pavia, Italy
    • Department of Biochemistry, University of Pavia, Pavia, Italy
    • Tel.: +39 382 987227; fax: +39 382 423108.
    • ,
  • Giovanna Valentini

      Affiliations

    • Department of Genetics and Microbiology, University of Pavia, Pavia, Italy
    • Department of Biochemistry, University of Pavia, Pavia, Italy
    • Tel.: +39 382 987227; fax: +39 382 423108.

References 

  1. Glader B. Hereditary hemolytic anemias due to enzyme disorders. In: Wintrobe’s clinical hematology. 11th ed.. Philadelphia: Lippincot Williams & Wilkins; 2004;p. 1115–1140
  2. Valentine WN, Tanaka KR, Miwa S. A specific erythrocyte glycolytic enzyme defect (pyruvate kinase) in three subjects with congenital non-spherocytic hemolytic anemia. Trans Assoc Am Physicians. 1961;74:100–110
  3. Beutler E, Gelbart T. Estimating the prevalence of pyruvate kinase deficiency from the gene frequency in the general white population. Blood. 2000;95:3585–3588
  4. Kayne FJ, Price NC. Amino acid effector binding to rabbit muscle pyruvate kinase. Arch Biochem Biophys. 1973;159:292–296
  5. Valentini G, Chiarelli LR, Fortin R, Speranza ML, Galizzi A, Mattevi A. The allosteric regulation of pyruvate kinase. J Biol Chem. 2000;275:18145–18152
  6. Gupta RK, Oesterling RM, Mildvan AS. Dual divalent cation requirement for activation of pyruvate kinase: essential roles of both enzyme- and nucleotide-bound metal ions. Biochemistry. 1976;15:2881–2887
  7. Boyer PD, Lardy HA, Phillips PH. The role of potassium in muscle phosphorylations. J Biol Chem. 1942;146:673–682
  8. Fothergill-Gilmore LA, Michels PA. Evolution of glycolysis. Prog Biophys Mol Biol. 1993;59:105–235
  9. Munoz ME, Ponce E. Pyruvate kinase: current status of regulatory and functional properties. Comp Biochem Physiol B Biochem Mol Biol. 2003;135:197–218
  10. Hall ER, Cottam GL. Isozymes of pyruvate kinase in vertebrates: their physical, chemical, kinetic and immunological properties. Int J Biochem. 1978;9:785–793
  11. Yamada K, Noguchi T. Regulation of pyruvate kinase M gene expression. Biochem Biophys Res Commun. 1999;256:257–262
  12. Takegawa S, Fujii H, Miwa S. Change of pyruvate kinase isozymes from M2- to L-type during development of the red cell. Br J Haematol. 1983;54:467–474
  13. Mazurek S, Boschek CB, Hugo F, Eigenbrodt E. Pyruvate kinase type M2 and its role in tumor growth and spreading. Semin Cancer Biol. 2005;15:300–308
  14. Noguchi T, Inoue H, Tanaka T. The M1- and M2- type isozymes of rat pyruvate kinase are produced from the same gene by alternative RNA splicing. J Biol Chem. 1986;261:13807–13812
  15. Satoh H, Tani K, Yoshida MC, Sasaki M, Miwa S, Fujii H. The human liver-type pyruvate kinase (PKL) gene is on chromosome 1 at band q21. Cytogenet Cell Genet. 1988;47:132–133
  16. Nowak T, Suelter C. Pyruvate kinase: activation by and catalytic role of the monovalent and divalent cations. Mol Cell Biochem. 1981;35:65–75
  17. Muirhead H, Clayden DA, Barford D, Lorimer CG, Fothergill-Gilmore LA, Schiltz E, et al. The structure of cat muscle pyruvate kinase. EMBO J. 1986;5:475–481
  18. Larsen TM, Laughlin LT, Holden HM, Rayment I, Reed GH. Structure of rabbit muscle pyruvate kinase complexed with Mn2+, K+, and pyruvate. Biochemistry. 1994;33:6301–6309
  19. Mattevi A, Valentini G, Rizzi M, Speranza ML, Bolognesi M, Coda A. Crystal structure of Escherichia coli pyruvate kinase type I: molecular basis of the allosteric transition. Structure. 1995;3:729–741
  20. Jurica MS, Mesecar A, Heath PJ, Shi W, Nowak T, Stoddard BL. The allosteric regulation of pyruvate kinase by fructose-1,6-bisphosphate. Structure. 1998;6:195–210
  21. Rigden DJ, Phillips SEV, Michels PAM, Fothergill-Gilmore LA. The structure of pyruvate kinase from Leishmania mexicana reveals details of the allosteric transition and unusual effector specificity. J Mol Biol. 1999;291:615–635
  22. Valentini G, Chiarelli LR, Fortin R, et al. Structure and function of human erythrocyte pyruvate kinase. Molecular basis of nonspherocytic hemolytic anemia. J Biol Chem. 2002;277:23807–23814
  23. Dombrauckas JD, Santarsiero BD, Mesecar AD. Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis. Biochemistry. 2005;44:9417–9429
  24. Zanella A, Bianchi P. Red cell pyruvate kinase (PK) deficiency: from genetics to clinical manifestations. Baillieres Best Pract Res Clin Haematol. 2000;13:57–81
  25. Wang C, Chiarelli LR, Bianchi P, et al. Human erythrocyte pyruvate kinase: characterization of the recombinant enzyme and a mutant form (R510Q) causing nonspherocytic hemolytic anemia. Blood. 2001;98:3113–3120
  26. Kahn A, Marie J. Pyruvate kinases from human erythrocytes and liver. Meth Enzymol. 1982;90:131–141
  27. Kilinc K, Ozer N. A rapid purification method for human erythrocyte pyruvate kinase. Biochem Med. 1984;32:296–302
  28. Noguchi T, Yamada K, Inoue H, Matsuda T, Tanaka T. The L- and R-type isozymes of rat pyruvate kinase are produced from a single gene by use of different promoters. J Biol Chem. 1987;262:14366–14371
  29. Kanno H, Fujii H, Miwa S. Structural analysis of human pyruvate kinase L-gene and identification of the promoter activity in erythroid cells. Biochem Biophys Res Commun. 1992;188:516–523
  30. Tani K, Fujii H, Nagata S, Miwa S. Human liver type pyruvate kinase: complete amino acid sequence and the expression in mammalian cells. Proc Natl Acad Sci U S A. 1988;85:1792–1795
  31. 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—-Met) affecting enzymatic stability in a pyruvate kinase variant (PK Tokyo) associated with hereditary hemolytic anemia. Proc Natl Acad Sci U S A. 1991;88:8218–8221
  32. Zanella A, Fermo E, Bianchi P, Valentini G. Red cell pyruvate kinase deficiency: molecular and clinical aspects. Br J Haematol. 2005;130:11–25
  33. Diez A, Gilsanz F, Martinez J, Perez-Benavente S, Meza NW, Bautista JM. Life-threatening nonspherocytic hemolytic anemia in a patient with a null mutation in the PKLR gene and no compensatory PKM gene expression. Blood. 2005;106:1851–1856
  34. Pissard S, Max-Audit I, Skopinski L, et al. Pyruvate kinase deficiency in France: a 3-year study reveals 27 new mutations. Br J Haematol. 2006;133:683–689
  35. Manco L, Ribeiro ML, Maximo V, et al. A new PKLR gene mutation in the R-type promoter region affects the gene transcription causing pyruvate kinase deficiency. Br J Haematol. 2000;110:993–997
  36. van Wijk R, van Solinge WW, Nerlov C, et al. Disruption of a novel regulatory element in the erythroid-specific promoter of the human PKLR gene causes severe pyruvate kinase deficiency. Blood. 2003;101:1596–1602
  37. Baronciani L, Beutler E. Molecular study of pyruvate kinase deficient patients with hereditary nonspherocytic hemolytic anemia. J Clin Invest. 1995;95:1702–1709
  38. Costa C, Albuisson J, Le TH, et al. Severe hemolytic anemia in a Vietnamese family, associated with novel mutations in the gene encoding for pyruvate kinase. Haematologica. 2005;90:25–30
  39. Fermo E, Bianchi P, Chiarelli LR, et al. Red cell pyruvate kinase deficiency: 17 new mutations of the PK-LR gene. Br J Haematol. 2005;129:839–846
  40. Lenzner C, Nurnberg P, Jacobasch G, Gerth C, Thiele BJ. Molecular analysis of 29 pyruvate kinase-deficient patients from central Europe with hereditary hemolytic anemia. Blood. 1997;89:1793–1799
  41. Demina A, Varughese KI, Barbot J, Forman L, Beutler E. Six previously undescribed pyruvate kinase mutations causing enzyme deficiency. Blood. 1998;92:647–652
  42. Pastore L, Della Morte R, Frisso G, et al. Novel mutations and structural implications in R-type pyruvate kinase-deficient patients from Southern Italy. Hum Mutat. 1998;11:127–134
  43. Zarza R, Alvarez R, Pujades A, et al. Molecular characterization of the PK-LR gene in pyruvate kinase deficient Spanish patients. Br J Haematol. 1998;103:377–382
  44. Manco L, Ribeiro ML, Almeida H, Freitas O, Abade A, Tamagnini G. PK-LR gene mutations in pyruvate kinase deficient Portuguese patients. Br J Haematol. 1999;105:591–595
  45. Baronciani L, Beutler E. Analysis of pyruvate kinase-deficiency mutations that produce nonspherocytic hemolytic anemia. Proc Natl Acad Sci U S A. 1993;90:4324–4327
  46. Kanno H, Wei DC, Chan LC, et al. Hereditary hemolytic anemia caused by diverse point mutations of pyruvate kinase gene found in Japan and Hong Kong. Blood. 1994;84:3505–3509
  47. Nakashima K, Miwa S, Fujii H, et al. Characterization of pyruvate kinase from the liver of a patient with aberrant erythrocyte pyruvate kinase, PK Nagasaki. J Lab Clin Med. 1977;90:1012–1020
  48. Hennekam RC, Beemer FA, Cats BP, Jansen G, Staal GE. Hydrops fetalis associated with red cell pyruvate kinase deficiency. Genet Couns. 1990;1:75–79
  49. Gilsanz F, Vega MA, Gomez-Castillo E, Ruiz-Balda JA, Omenaca F. Fetal anaemia due to pyruvate kinase deficiency. Arch Dis Child. 1993;69:523–524
  50. Afriat R, Lecolier B, Prehu MO, et al. Prenatal diagnosis of homozygous pyruvate kinase deficiency. J Gynecol Obstet Biol Reprod (Paris). 1995;24:81–84
  51. van Solinge WW, Kraaijenhagen RJ, Rijksen G, et al. Molecular modelling of human red blood cell pyruvate kinase: structural implications of a novel G1091 to A mutation causing severe nonspherocytic hemolytic anemia. Blood. 1997;90:4987–4995
  52. Ferreira P, Morais L, Costa R, et al. Hydrops fetalis associated with erythrocyte pyruvate kinase deficiency. Eur J Pediatr. 2000;159:481–482
  53. Sedano IB, Rothlisberger B, Deleze G, et al. PK Aarau: first homozygous nonsense mutation causing pyruvate kinase deficiency. Br J Haematol. 2004;127:364–366
  54. Boivin P, Ottenwaelter T. Anémie hémolytique héreditaire par déficit en pyruvate-kinase: pronostic des formes neonatales. Nouv Presse Med. 1982;11:917–919
  55. Amankwah KS, Dick BW, Dodge S. Hemolytic anemia and pyruvate kinase deficiency in pregnancy. Obstet Gynecol. 1980;55l:42S–44S
  56. Dolan LM, Ryan M, Moohan J. Pyruvate kinase deficiency in pregnancy complicated by iron overload. BJOG. 2002;109:844–846
  57. Fanning J, Hinkle RS. Pyruvate kinase deficiency hemolytic anemia: two successful pregnancy outcomes. Am J Obstet Gynecol. 1985;153:313–314
  58. Esen UI, Olajide F. Pyruvate kinase deficiency: an unusual cause of puerperal jaundice. Int J Clin Pract. 1998;52:349–350
  59. Oski FA, Marshall BE, Cohen PJ, Sugerman HJ, Miller LD. The role of the left-shifted or right-shifted oxygen-hemoglobin equilibrium curve. Ann Intern Med. 1971;74:44–46
  60. Mentzer WC, Baehner RL, Schmidt-Schonbeth H, Robinson SH, Nathan DG. Selective reticulocyte destruction in erythrocyte pyruvate kinase deficiency. J Clin Invest. 1971;50:688–699
  61. Matsumoto N, Ishihara T, Nakashima K, Miwa S, Uchino F. Sequestration and destruction of reticulocyte in the spleen in pyruvate kinase deficiency hereditary nonspherocytic hemolytic anemia. Nippon Ketsueki Gakkai Zasshi. 1972;35:525–537
  62. Sampietro M, Tavazzi D, Fermo E, Bianchi P, Zanella A. Hyperbilirubinemia in pyruvate kinase deficiency: the role of Gilbert’s syndrome. Blood. 2003;102:258a;abstract
  63. Kanno H, Fujii H, Tsujino G, Miwa S. Molecular basis of impaired pyruvate kinase isozyme conversion in erythroid cells: a single amino acid substitution near the active site and decreased mRNA content of the R-type PK. Biochem Biophys Res Commun. 1993;192:46–52
  64. Lenzner C, Nurnberg P, Thiele BJ, et al. Mutations in the pyruvate kinase L gene in patients with hereditary hemolytic anemia. Blood. 1994;83:2817–2822
  65. Beutler E. Red cell metabolism: a manual of biochemical methods. New York: Grune & Stratton, Inc.; 1984;
  66. Rouger H, Girodon E, Goossens M, Galacteros F, Cohen Solal M. PK Mondor: prenatal diagnosis of a frameshift mutation in the LR pyruvate kinase gene associated with severe hereditary non-spherocytic haemolytic anaemia. Prenat Diagn. 1996;16:97–104
  67. Kanno H, Fujii H, Wei DC, et al. Frame shift mutation, exon skipping, and a two-codon deletion caused by splice site mutations account for pyruvate kinase deficiency. Blood. 1997;89:4213–4218
  68. Cotton F, Bianchi P, Zanella A, et al. A novel mutation causing pyruvate kinase deficiency responsible for a severe neonatal respiratory distress syndrome and jaundice. Eur J Pediatr. 2001;160:523–524
  69. Zanella A, Bianchi P, Baronciani L, et al. Molecular characterization of PK-LR gene in pyruvate kinase deficient patients. Blood. 1997;89:3847–3852
  70. Zanella A, Bianchi P, Fermo E, et al. Molecular characterization of the PK-LR gene in sixteen pyruvate kinase-deficient patients. Br J Haematol. 2001;13:43–48
  71. Hilgard P, Gerken G. Liver cirrhosis as a consequence of iron overload caused by nonspherocytic haremolitic anaemia. World J Gastroenterol. 2005;11:1241–1244
  72. Pendergrass DC, Williams R, Blair JB, Fenton AW. Mining for allosteric information: natural mutations and positional sequence conservation in pyruvate kinase. IUBMB Life. 2006;58:31–38
  73. van Wijk R, van Solinge WW. Pyruvate kinase deficiency: genotype to phenotype. Hematology (EHA Educ Program). 2006;2:55–62
  74. van Wijk, van Wesel AC, Thomas AA, Rijksen G, van Solinge WW. Ex vivo analysis of aberrant splicing induced by two donor site mutations in PKLR of a patient with severe pyruvate kinase deficiency. Br J Haematol. 2004;125:253–263
  75. van Solinge WW, van Wijk HA, Kraaijenhagen RJ, Rijksen G, Nielsen FC. Novel mutations in the human red cell type pyruvate kinase gene: Two promoter mutations in cis, a splice site mutation, a nonsense- and three missense mutations. Blood. 1997;90:1197;abstract
  76. Neubauer B, Lakomek M, Winkler H, Parke M, Hofferbert S, Schroter W. Point mutations in the L-type pyruvate kinase gene of two children with hemolytic anemia caused by pyruvate kinase deficiency. Blood. 1991;77:1871–1875
  77. Kanno H, Fujii H, Hirono A, Omine M, Miwa S. Identical point mutations of the R-type pyruvate kinase (PK) cDNA found in unrelated PK variants associated with hereditary hemolytic anemia. Blood. 1992;79:1347–1350
  78. Lakomek M, Huppke P, Neubauer B, Pekrun A, Winkler H, Schröter W. Mutations in the R-type pyruvate kinase gene and altered enzyme kinetic properties in patients with hemolytic anemia due to pyruvate kinase deficiency. Ann Hematol. 1994;68:253–260
  79. Aizawa S, Kohdera U, Hiramoto M, et al. Ineffective erythropoiesis in the spleen of a patient with pyruvate kinase deficiency. Am J Hematol. 2003;74:68–72
  80. Aizawa S, Harada T, Kanbe E, Tsuboi I, Aisaki K, Fujii H, et al. Ineffective erythropoiesis in mutant mice with deficient pyruvate kinase activity. Exp Hematol. 2005;33:1292–1298
  81. Tanaka KR, Zerez CR. Red cell enzymopathies of the glycolytic pathway. Semin Hematol. 1990;27:165–185
  82. Pincus M, Stark RA, O’Neill JH. Ischaemic stroke complicating pyruvate kinase deficiency. Int Med J. 2003;33:473–474
  83. Zanella A, Berzuini A, Colombo MB, et al. Iron status in red cell pyruvate kinase deficiency: study of Italian cases. Br J Haematol. 1993;83:485–490
  84. Zanella A, Bianchi P, Iurlo A, et al. Iron status and HFE genotype in erythrocyte pyruvate kinase deficiency: study of Italian cases. Blood Cells Mol Dis. 2001;27:653–661
  85. Marshall SR, Saunders PW, Hamilton PJ, Taylor PR. The dangers of iron overload in pyruvate kinase deficiency. Br J Haematol. 2003;120:1090–1091
  86. Pootrakul P, Vongsmasa V, La-ongpanich P, Wasi P. Serum ferritin levels in thalassaemias and the effect of splenectomy. Acta Haematol. 1981;66:244–250
  87. Porter JB. Practical management of iron overload. Br J Haematol. 2001;115:239–252
  88. Piperno A, Sampietro M, Pietrangelo A, et al. Heterogeneity of hemochromatosis in Italy. Gastroenterology. 1998;114:996–1002

PII: S0268-960X(07)00002-1

doi: 10.1016/j.blre.2007.01.001

Blood Reviews
Volume 21, Issue 4 , Pages 217-231 , July 2007

Article Tools

* Image Usage & Resolution