Elsevier

Blood Reviews

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

Review
Pyruvate kinase deficiency: The genotype-phenotype association

https://doi.org/10.1016/j.blre.2007.01.001Get rights and content

Summary

Red cell pyruvate kinase (PK) deficiency is the most frequent enzyme abnormality of glycolysis causing chronic non-spherocytic haemolytic anaemia. The disease is transmitted as an autosomal recessive trait, clinical symptoms usually occurring in compound heterozygotes for two mutant alleles and in homozygotes. The severity of haemolysis is highly variable, ranging from very mild or fully compensated forms to life-threatening neonatal anaemia necessitating exchange transfusions. Erythrocyte PK is synthesised under the control of the PK-LR gene located on chromosome 1. One hundred eighty different mutations in PK-LR gene, mostly missense, have been so far reported associated to PK deficiency. First attempts to delineate the genotype-phenotype association were mainly based on the analysis of the enzyme’s three-dimensional structure and the observation of the few homozygous patients. More recently, the comparison of the recombinant mutants of human red cell PK with the wild-type enzyme has enabled the effects of amino acid replacements on the enzyme molecular properties to be determined. However, the clinical manifestations of red cell enzyme defects are not merely dependent on the molecular properties of the mutant protein but rather reflect the complex interactions of additional factors, including genetic background, concomitant functional polymorphisms of other enzymes, posttranslational or epigenetic modifications, ineffective erythropoiesis and differences in splenic function.

Introduction

Red cell pyruvate kinase (PK) deficiency, transmitted as an autosomal recessive trait, is the most frequent enzyme abnormality of the glycolytic pathway, and the most common cause of hereditary non spherocytic haemolytic anaemia together with class I glucose-6-phosphate dehydrogenase deficiency.1 Since the first detection in the early ’60 s,2 about 500 cases have been described, but many more remain unreported in the absence of unusual clinical or molecular features. The severity of haemolysis is highly variable, ranging from very mild or fully compensated forms to life-threatening neonatal anaemia necessitating exchange transfusions. PK deficiency has a world-wide geographical distribution, with an estimated prevalence of 1:20,000 in the general white population as assessed by gene frequency studies.3

Section snippets

Pyruvate kinase: structure and function

Pyruvate kinase (PK; ATP: pyruvate 2-o-phosphotransferase, EC 2.7.1.40) is a rate-controlling glycolytic enzyme that catalyses the irreversible conversion of phosphoenolpyruvate (PEP) to pyruvate, coupled to the synthesis of one molecule of ATP.4, 5PEP+MgADP+H+Mg2+,K+MgATP+PyruvateThe enzyme requires for its activity two equivalents of bivalent cations, usually Mg2+or Mn2+, and one equivalent of monovalent cations, usually K+.6, 7 The PK-catalysed reaction is the second ATP-generating step of

Gene and genetics

The PK-LR gene (over 9.5 kb) is located on chromosome 1q2115 where it directs tissue-specific transcription for both the liver-specific (LPK) and the red cell-specific (RPK) isoenzyme by the use of alternate promoters.28, 29 The codifying region is split into twelve exons, ten of which are shared by the two isoforms, while exons 1 and 2 are specific for the erythrocyte and the hepatic isoenzyme respectively.28, 30, 31

The cDNA encoding RPK is 2060 bp long and codes for 574 amino acids.31 In the

Clinical, haematological and diagnostic features of PK deficiency

Although abnormalities in PK-LR gene may result in alterations of both erythrocyte and liver enzyme, clinical symptoms are confined to red blood cells, the hepatic deficiency being usually compensated by the persistent enzyme synthesis in hepatocytes.47 Clinical manifestations of PK deficiency comprise the usual hallmarks of lifelong chronic haemolysis. The severity of clinical picture is variable, ranging from mild or fully compensated forms to life-threatening neonatal anaemia necessitating

The genotype-phenotype association

The biochemical and clinical consequences of PK mutations can be deduced from the investigation of the few homozygous patients and, to a lesser extent, from the study of larger series of compound heterozygotes grouped according to their clinical phenotype. More recently, the production and characterisation of the recombinant mutant proteins of human RPK made it possible to define the effects of amino acid replacements on the stability and kinetic properties of PK and helped to correlate

Clinical variability and phenotypic modifiers

Although in some cases there is a clear and direct correlation between the patient’s genotype and phenotype, caution is needed in predicting the clinical consequences of molecular abnormalities; in fact, the clinical manifestations of red cell enzyme defects reflect the complex interactions of physiological and environmental factors including genetic background, concomitant functional polymorphisms of other enzymes, posttranslational or epigenetic modifications, ineffective erythropoiesis and

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      We were able to redefine her previous diagnosis on account of the molecular study of the PKLR gene, which highlights the difficulties in the differential diagnosis between CDA and PKD in absence of PK enzyme assay. The proband had two missense variants in the PKLR gene, one of which (Arg486Trp) is described to have a high frequency in Southern Europe and is associated at the homozygote state with a “mild phenotype” [22]. The other, not previously described variant (Asp221His) would be responsible for the impossibility of oligomerization of the tetramer according to the results of molecular modeling.

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