Mutations in the pyruvate kinase L gene in patients with hereditary hemolytic anemia

Lenzner, Claudia; Nürnberg, Peter; Thiele, B; Reis, André; Brabec, V; Sakalová, A; Jacobasch, G

doi:10.1182/blood.v83.10.2817.2817

Cited by 52 publications

(30 citation statements)

References 19 publications

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“…Care must be taken in interpreting in vitro PK assays: contamination with normal donor red cells in recently transfused patients and incomplete leucocyte removal (leucocyte PK activity is 300 times higher than that of RPK) may result in a false normal red cell enzyme activity. Moreover, the M 2 isoenzyme may be expressed in mature red cells of some patients (Kanno et al, 1993a;Lenzner et al, 1994a), contributing to the measured activity. Finally, kinetically abnormal mutant PKs, although ineffective in vivo, may display normal or even higher catalytic activity under the optimal, artificial conditions of laboratory assays (Zanella & Bianchi, 2000); this possibility makes it advisable to determine the enzyme activity at both high and low phosphoenol pyruvate concentration (Beutler, 1984).…”

Section: Haematological Featuresmentioning

confidence: 99%

Red cell pyruvate kinase deficiency: molecular and clinical aspects

et al. 2005

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SummaryRed cell pyruvate kinase (PK) deficiency is the most frequent enzyme abnormality of the glycolytic pathway causing hereditary non-spherocytic haemolytic anaemia. The degree of haemolysis varies widely, ranging from very mild or fully compensated forms, to life-threatening neonatal anaemia and jaundice necessitating exchange transfusions. Erythrocyte PK is synthesized under the control of the PK-LR gene located on chromosome 1. To date, more than 150 different mutations in the PK-LR gene have been associated with PK deficiency. First attempts to delineate the biochemical and clinical consequences of the molecular defect were mainly based on the observation of the few homozygous patients and on the analysis of the three-dimensional structure of the enzyme. 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 and help to correlate genotype to clinical phenotype.

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Section: Haematological Featuresmentioning

confidence: 99%

Red cell pyruvate kinase deficiency: molecular and clinical aspects

et al. 2005

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“…Domains A, B and C are shown in green, blue and red, respectively. The spheres outline the residues whose mutation in the human R PK causes the non-spherocytic haemolytic anaemia ( [16][17][18] and references therein). The amino acid sequence identity between human R and E. coli PK is 51%.…”

Section: Catalytic Sitementioning

confidence: 99%

“…Deficiency of the human erythrocyte R PK is the most common cause of the hereditary non-spherocytic haemolytic anaemia [10], a congenital disease with severe clinical manifestations, leading to occasional death in the neonatal period. Over the past years, the PK gene of many patients has been sequenced, revealing that in most cases a single site mutation is causing the enzyme deficiency ( [16][17][18] and references therein). The effect of many of these pathological PK mutations can now be rationalised on the basis of the described allosteric transition mechanism.…”

Section: Molecular Abnormalities and Anaemiamentioning

confidence: 99%

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The allosteric regulation of pyruvate kinase

1996

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Crystallographic and mutagenesis studies have unravelled the general features of the allosteric transition mechanism in pyruvate kinase. The enzyme displays a dramatic conformational change in going from the T-to the R-state. All three domains forming each subunit of the tetrameric enzyme undergo simultaneous and concerted rotations, in such a way that all subunit and domain interfaces are modified. This mechanism is unprecedented since in all tetrameric allosteric enzymes, characterised at atomic resolution, at least one of the domain or subunit interfaces remains unchanged on the T-to R-state transition. The molecular mechanism of allosteric regulation here proposed provides a rationale for the effect of single site mutations observed in the human erythrocyte pyruvate kinase associated with a congenital anaemia.Key words." Glycolysis; Metabolism regulation; X-ray crystallography; Pyruvate kinase whereas the L PK is additionally controlled by phosphorylation on a N-terminal Ser residue which causes a decrease in the affinity for the PEP and FBP activators [3]. More unusual is the muscle M1 protein [6] which is the only known PK displaying hyperbolic kinetics and no allosteric control.While the structure of the cat M1 isoenzyme was determined by Muirhead and coworkers several years ago [6], little information was available about the allosteric transition in PK. Substantial progress in this respect has been observed over the last few years with further refinement of the M1 isoenzyme model [7], and with the X-ray structure determination of the FBP-dependent E. coli PK, in the inactive T-state [8]. Furthermore, insight into the enzyme regulatory properties has been provided by mutagenesis studies [9] and by the characterisation of several R PK variants from patients with congenital anaemia [10].

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“…In 1988 a full-length PK-L cDNA was isolated and its sequence determined (Tani et al, 1988). Several mutations in the PK-LR gene have been described as involved in PK deficiency (Baronciani & Beutler, 1993a, b;Kanno et al, 1991Kanno et al, , 1992Kanno et al, , 1993aLenzner et al, 1994;Neubauer et al, 1991). The spatial structure of cat muscle (Muirhead et al, 1986) and that of rabbit muscle PK (Larsen et al, 1994) were resolved respectively at 2 .…”

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confidence: 99%

Five unknown mutations in the LR pyruvate kinase gene associated with severe hereditary nonspherocytic haemolytic anaemia in France

et al. 1996

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A survey of PK-deficient patients by molecular biology techniques has been performed in France in 26 unrelated families, in which at least one mutation has been characterized. The patients, of European or North African origin, exhibited approximatively 10% of PK activity. Among the PK-R mutants described, mutation G1529-->A (Arg-509-->Gln) was the most frequent. The strategy followed for the description of PK mutants in France firstly involves determination of this mutation by PCR amplification and restriction enzyme digestion and, secondly, the sequencing of the gene for negative samples. Study of the mutation at residue 509 in 26 unrelated families indicated that 10/52 defective alleles possessed this mutation. Our study described seven different mutations; five of these have not as yet been documented. Two frameshift mutations were found: the deletion of one G base in a repetition of four Gs in position 1231-1234 (PK Mondor), del C-1527 (PK Rouen), and three missense mutations: G382-->C (Ala-114-->Pro) (PK Val-de-Marne), C398-->T (Ser-119-->Phe) (PK Beaujon), A1217-->G (Asn-392-->Ser) (PK Paris). Two mutations which were detected have been reported previously: C760-->T (Glu-240-->End) and G1529-->A (Arg-509-->Gln.

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Mutations in the pyruvate kinase L gene in patients with hereditary hemolytic anemia

Cited by 52 publications

References 19 publications

Red cell pyruvate kinase deficiency: molecular and clinical aspects

Red cell pyruvate kinase deficiency: molecular and clinical aspects

The allosteric regulation of pyruvate kinase

Five unknown mutations in the LR pyruvate kinase gene associated with severe hereditary nonspherocytic haemolytic anaemia in France

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