G→T transition 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

Beutler, Ernest; Westwood, Beryl; Zwieten, Rob van; Roos, Dirk

doi:10.1002/(sici)1098-1004(1997)9:3<282::aid-humu13>3.0.co;2-z

Cited by 15 publications

(7 citation statements)

References 20 publications

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“…Erythrocytosis has been reported in families who have been described with increased ATP levels associated with low 2.3 BPG levels with autosomal dominant inheritance. Elevated pyruvate kinase activity has been associated, but the relationship is not fully explained . These extremely rare described defects should perhaps be considered as causes of congenital erythrocytosis.…”

Section: Secondary Congenital Erythrocytosismentioning

confidence: 99%

Congenital erythrocytosis

McMullin

2016

Int J Lab Hematology

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Summary Introduction Congenital erythrocytosis is by definition present from birth. Patients frequently present in childhood or as young adults and a family history may be present. The erythrocytosis can be primary where there is a defect in the erythroid compartment of secondary where increased erythropoietin production produced due to the defect leads to an erythrocytosis. Material and methods Primary causes include erythropoietin receptor mutations. Congenital secondary causes include mutations in the genes involved in the oxygen‐sensing pathway and haemoglobins with abnormal oxygen affinity. Investigations for the cause include an erythropoietin level, oxygen dissociation curve, haemoglobin electrophoresis and sequencing for known gene variants. Results The finding of a known or new molecular variant confirms a diagnosis of congenital erythrocytosis. A congenital erythrocytosis may be an incidental finding but nonspecific symptoms are described. Major thromboembolic events have been noted in some cases. Low‐dose aspirin and venesection are therapeutic manoeuvres which should be considered in managing these patients. Conclusions Rare individuals presenting often at a young age may have a congenital erythrocytosis. Molecular investigation may reveal a lesion. However, in the majority, currently no defect is identified.

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Section: Secondary Congenital Erythrocytosismentioning

confidence: 99%

Congenital erythrocytosis

McMullin

2016

Int J Lab Hematology

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“…The authors concluded that PK hyperactivity likely resulted from a shift in the R(elaxed) versus T(ight) equilibrium towards the R(elaxed) form. In line with these altered kinetic properties a single nucleotide substitution in exon 2 of PKLR (c.110G>A) was later identified [10]. This missense mutation predicts an amino acid substitution at residue 37 (p.Gly37Glu) that was postulated to interfere with phosphorylation of Ser42.…”

Section: Resultsmentioning

confidence: 96%

“…In the first described family [7], increased PK activity was found to be because of altered enzymatic properties of PK-R [9]. In line with these findings a heterozygous missense mutation in PKLR was later identified [10]. In the second family [8] increased PK activity was attributed to persistent expression of the fetal isozyme PK-M2 [11,12].…”

Section: Introductionmentioning

confidence: 76%

Novel type of red blood cell pyruvate kinase hyperactivity predicts a remote regulatory locus involved in PKLR gene expression

et al. 2014

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Red blood cell pyruvate kinase (PK-R) is a key regulatory enzyme of red cell metabolism. Hereditary deficiency of PK-R is caused by mutations in the PKLR gene, leading to chronic nonspherocytic hemolytic anemia. In contrast to PK deficiency, inherited PK hyperactivity has also been described. This very rare abnormality of RBC metabolism has been documented in only two families and appears to be without clinical consequences. Thus far, it has been attributed to either a gain of function mutation in PKLR or to persistent expression of the fetal PK isozyme PK-M2 in mature red blood cells. We here report on a novel type of inherited PK hyperactivity that is characterized by solely increased expression of a kinetically normal PK-R. In line with the latter, no mutations were detected in PKLR. Mutations in regulatory regions as well as variations in PKLR copy number were also absent. In addition, linkage analysis suggested that PK hyperactivity segregated independently from the PKLR locus. We therefore postulate that the causative mutation resides in a novel yet-unidentified locus, and upregulates PKLR gene expression. Other mutations of the same locus may be involved in those cases of PK deficiency that fail to reveal mutations in PKLR.

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“…Erythrocytosis has been also reported in families who have been described with increased ATP levels associated with low 2,3-BPG levels with autosomal dominant inheritance 27 .…”

Section: Other Secondary Causes Of Hereditary Erythrocytosismentioning

confidence: 90%

Diagnostic workflow for hereditary erythrocytosis and thrombocytosis

McMullin

2019

Hematology

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In the patient presenting with an elevated blood count who does not have an acquired clonal disorder causing a myeloproliferative neoplasm, hereditary erythrocytosis or hereditary thrombocytosis needs to be considered as a possible explanation. A young patient and/or those with a family history of myeloproliferative neoplasm should specifically raise this possibility. Among the causes of hereditary erythrocytosis are mutations in the genes in the oxygen sensing pathway and high-affinity hemoglobins. Hereditary thrombocytosis has been shown to be accounted for by mutations in THPO, MPL, and JAK2 genes. In those who have a possible hereditary erythrocytosis or thrombocytosis, the investigative pathway includes specific investigation to rule out the more common acquired clonal disorders, and, if indicated, other secondary causes, measurement of specific cytokines as indicated, and search for specific identified molecular lesions that have been shown to cause these hereditary disorders. There remain individuals who appear to have a hereditary disorder in whom a genetic lesion cannot currently be identified.

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G→T transition 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

Cited by 15 publications

References 20 publications

Congenital erythrocytosis

Congenital erythrocytosis

Novel type of red blood cell pyruvate kinase hyperactivity predicts a remote regulatory locus involved in PKLR gene expression

Diagnostic workflow for hereditary erythrocytosis and thrombocytosis

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