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

Rouger, H.; Valentin, Colette; Craescu, Constantin T.; Galactéros, Frédéric; Cohen-Solal, M.

doi:10.1046/j.1365-2141.1996.405941.x

Cited by 22 publications

(6 citation statements)

References 16 publications

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“…Studies in Western/Northern European PK‐deficient patients (Lenzner et al , 1994b, 1997; Baronciani et al , 1995; Baronciani & Beutler, 1995; Rouger et al , 1996) found the 1529G → A to be the most common mutation; however, in Italian patients (Zannela et al , 1997) the most frequent mutation was the 1456C → T. In our study, 7/18 affected alleles had the 1456C → T mutation and the 1529G → A mutation was not found. These data suggest regional differences, with a Western/Northern European prevalence of the 1529A → G and a Southern European prevalence of the 1456C → T mutation.…”

Section: Discussioncontrasting

confidence: 71%

“…In mammals there are only two different PK genes: the PK‐M gene that codes for the isoenzymes M1 (muscle and brain) and M2 (fetal and most adult tissues) using alternative RNA splicing (Noguchi et al , 1986) and the PK‐LR gene, that codes for the L‐type (liver) and R‐type (erythrocyte) isoenzymes using two different tissue‐specific promoters (Noguchi et al , 1987). More than 70 mutations have been identified in the coding and flanking regions of the PK‐LR gene of PK‐deficient patients, most of them being compound heterozygotes (Baronciani & Beutler, 1993, 1995; Baronciani et al , 1995; Zannela et al , 1997; Kanno et al , 1991, 1992, 1993a, b, c, 1994a, b, 1997; Lenzner et al , 1994b, 1997; Neubauer et al , 1991; Rouger et al , 1996; Uenaka et al , 1995; van Solinge et al , 1997).…”

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PK‐LR gene mutations in pyruvate kinase deficient Portuguese patients

et al. 1999

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Summary.In nine unrelated Portuguese patients with pyruvate kinase (PK) deficient anaemia, whose symptoms ranged from a mild chronic haemolytic anaemia to a severe anaemia presenting at birth and requiring multiple transfusions, the PK-LR gene mutations were identified and correlated with their phenotypes. Five different mutations were identified, three of them for the first time: a missense mutation 1670G → C on exon 12 and two 5 0 splice donor site (GT) mutations on intron 8 [IVS8(þ2)T → G] and intron 10 [IVS10(þ1)G → C]. Two previously described missense mutations, 1456C → T and 993C → A, were also found. The genotype/phenotype correlation showed that patients with two missense mutations or with a missense mutation and a splicing mutation had a mild haemolytic anaemia. The three patients with severe anaemia, who were transfusion dependent until splenectomy, were homozygous for the splicing site mutations IVS10(þ1)G → C or IVS8(þ2)T → G.Keywords: pyruvate kinase deficiency, human PK-LR gene mutations, haemolytic anaemia, splice site, Portugal.Pyruvate kinase (PK EC 2.7.1.40) deficiency is the most common enzyme abnormality in the erythrocyte glycolytic pathway causing hereditary nonspherocytic haemolytic anaemia (HNSHA). The PK-deficient anaemia is transmitted as an autosomal recessive disorder with a heterogenous clinical phenotype, ranging from a mild chronic haemolytic anaemia to a severe anaemia presenting at birth and requiring exchange transfusion. Splenectomy is effective in decreasing haemolysis in most patients. Heterozygotes are usually asymptomatic, with a 30-50% decrease in the PK activity levels (Miwa et al, 1979). PK deficiency was first described by Valentine et al (1961) and since then more than 400 cases have been reported, with the biochemical characteristics of the residual enzyme differing markedly between patients. The International Committee for Standardization in Haematology (ICSH) established the standard methods for enzymatic studies; however, the low activity, different stability and the hybrid tetramers formed in the compound heterozygous causes difficulty in characterization of the PK variants (Miwa et al, 1979). A molecular approach, identifying the gene mutations, enables a better characterization of the PK-deficient patients with a more precise genotype/phenotype correlation.It is also useful for diagnosis among transfusion-dependent patients with chronic haemolytic anaemia and prenatal diagnosis.Four PK isoenzymes have been described in mammals, M1, M2, L and R, which are tissue specific and differ in their enzymatic properties (Imamura & Tanaka, 1972). In mammals there are only two different PK genes: the PK-M gene that codes for the isoenzymes M1 (muscle and brain) and M2 (fetal and most adult tissues) using alternative RNA splicing (Noguchi et al, 1986) and the PK-LR gene, that codes for the L-type (liver) and R-type (erythrocyte) isoenzymes using two different tissue-specific promoters (Noguchi et al, 1987). More than 70 mutations have been identified in the coding and flank...

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Section: Discussioncontrasting

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PK‐LR gene mutations in pyruvate kinase deficient Portuguese patients

et al. 1999

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“…DNA was prepared by standard techniques ( Lemarchandel et al , 1992 ). The gene was amplified in several parts using oligonucleotide primers located exclusively in the introns ( Rouger et al , 1996 ) and sequenced (see Table I for the primers used and Fig 1 for the procedure followed). A fragment bearing the mutation was detected by single‐stranded conformation polymorphism (SSCP) analysis ( Hertzberg et al , 1998 ).…”

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confidence: 99%

A new sickle cell disease phenotype associating Hb S trait, severe pyruvate kinase deficiency (PK Conakry), and an α2 globin gene variant (Hb Conakry)

et al. 1998

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A Guinean woman, hetererozygous for haemoglobin (Hb) S, was studied because of episodes of marked anaemia, repeated typical metaphyseal painful crises and haemosiderosis. Her sickling syndrome resulted from the association of Hb S trait with a severe pyruvate kinase deficiency leading to a 2,3‐DPG concentration of twice normal levels. Sequence of the PK‐R gene revealed an undescribed mutation in the homozygous or hemizygous state within exon 5 (nucleotide 2670 C → A), leading to the interchange of Ser 130 into Tyr (PK Conakry). In addition, the patient carried a new haemoglobin variant, Hb Conakry [α80(F1) Leu → Val], which seemed to have a mild effect. The high intraerythrocytic 2,3‐DPG concentration induced by the PK deficiency resulted in a decreased oxygen affinity which favoured sickling to a level almost similar to that of Hb S/C compound heterozygous patients. This was confirmed by oxygen binding measurements of Hb A/Hb S erythrocytes in which 2,3‐DPG content was modified in vitro. Hysteresis between deoxy‐ and reoxygenation curves, as well as increase in the nmax value, demonstrated that the extent of HbS polymerization in the propositus was almost the same as that of RBCs from a homozygous sickle cell patient or those of an A/S heterozygous patient with an artificial in vitro increase of 2,3‐DPG concentration.

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“…The cloning of the R‐type cDNA has enabled the study of this enzymopathy at the DNA level ( Tani et al , 1988 ; Kanno et al , 1991 ), and, up to now, about 80 mutations involved in the deficient PK‐LR gene have been described ( Baronciani et al , 1996 ; Baronciani & Beutler, 1993a, b; Kanno et al , 1991 , 1992, 1993a, b, c; Lakomek et al , 1994 ; Lenzner et al , 1994 , 1997; Neubauer et al , 1991 ; Bianchi et al , 1994 , 1995; Rouger et al , 1996 ). This is the first report of a complete mutation analysis of the PK‐LR gene performed in 12 unrelated PKD patients from Spain.…”

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Molecular characterization of the PK‐LR gene in pyruvate kinase deficient Spanish patients

Zarza¹,

Alvarez²,

Pujades³

et al. 1998

Br J Haematol

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The PK‐LR gene has been studied in 12 unrelated patients with red cell pyruvate kinase deficiency and hereditary nonspherocytic haemolytic anaemia (CNSHA). The entire codifying region of the R‐type PK gene and the flanking intronic regions were analysed by single‐stranded conformation polymorphism (SSCP) followed by direct sequencing of abnormal DNA. 10 different mutations were identified in 22/24 alleles at risk. Eight of these were missense mutations that caused the following single amino acid changes: G514C (172Glu‐Gln), G1010A (337Arg‐Gln), G1015C (339Asp‐Gln), T1070C (357Ile‐Thr), C1223T (408Thr‐Ile), G1291A (431Ala‐Thr), C1456T (486Arg‐Trp) and G1595A (532Arg‐Gln). Two were nonsense mutations: G721T (241Glu‐Stop) and C1675T (559Arg‐Stop). 7/22 alleles demonstrated the same C1456→ T mutation. The study of the polymorphic site at nucleotide (nt) 1705 performed in all cases disclosed a 1705 C/C mutation in 10 and a 1705 A/C mutation in three. This is the first report on the presence of several different L‐type PK gene mutations within Spanish population. Furthermore, from the PK gene mutations found, six were unique and not previously described (1015C, 1070C, 1223T, 1291A, 1595A and 1675T) and one (C1456T) seems to be predominant in Spain. Interestingly, no case with the 1529A mutation commonly found in Northern European populations was present here.

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

Cited by 22 publications

References 16 publications

PK‐LR gene mutations in pyruvate kinase deficient Portuguese patients

PK‐LR gene mutations in pyruvate kinase deficient Portuguese patients

A new sickle cell disease phenotype associating Hb S trait, severe pyruvate kinase deficiency (PK Conakry), and an α2 globin gene variant (Hb Conakry)

Molecular characterization of the PK‐LR gene in pyruvate kinase deficient Spanish patients

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