Retarded and Aberrant Splicings Caused by Single Exon Mutation in a Phosphoglycerate Kinase Variant

Ookawara, Tomomi; Dave, Vinnidhy; Willems, Patrick J.; Martin, Jean‐Jacques; Barsy, Thierry de; Matthys, E; Yoshida, Akira

doi:10.1006/abbi.1996.0089

Cited by 26 publications

(7 citation statements)

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“…As a consequence, the consensus 5′ splicing sequence AGgt is changed to a nonconsensus sequence CGgt leading to a reduction of splicing efficiency (approximately only 10%) [27]. Thus, the highly reduced activity found in cells (8% in muscle, 6% in RBC) is most likely a result of a low content of PGK1, due to a reduced maturation of its mRNA.…”

Section: Discussionmentioning

confidence: 99%

Molecular Insights on Pathogenic Effects of Mutations Causing Phosphoglycerate Kinase Deficiency

et al. 2012

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Phosphoglycerate kinase (PGK) catalyzes an important ATP-generating step in glycolysis. PGK1 deficiency is an uncommon X-linked inherited disorder, generally characterized by various combinations of non-spherocytic hemolytic anemia, neurological dysfunctions, and myopathies. Patients rarely exhibit all three clinical features. To provide a molecular framework to the different pathological manifestations, all known mutations were reviewed and 16 mutant enzymes, obtained as recombinant forms, were functionally and structurally characterized. Most mutations heavily affect thermal stability and to a different extent catalytic efficiency, in line with the remarkably low PGK activity clinically observed in the patients. Mutations grossly impairing protein stability, but moderately affecting kinetic properties (p.I47N, p.L89P, p.C316R, p.S320N, and p.A354P) present the most homogeneous correlation with the clinical phenotype. Patients carrying these mutations display hemolytic anemia and neurological disorders, and,except for p.A354P variant, no myopaty. Variants highly perturbed in both catalytic efficiency (p.G158V, p.D164V, p.K191del, D285V, p.D315N, and p.T378P) and heat stability (all, but p.T378P) result to be mainly associated with myopathy alone. Finally, mutations faintly affecting molecular properties (p.R206P, p.E252A, p.I253T, p.V266M, and p.D268N) correlate with a wide spectrum of clinical symptoms. These are the first studies that correlate the clinical symptoms with the molecular properties of the mutant enzymes. All findings indicate that the different clinical manifestations associated with PGK1 deficiency chiefly depend on the distinctive type of perturbations caused by mutations in the PGK1 gene, highlighting the need for determination of the molecular properties of PGK variants to assist in prognosis and genetic counseling. However, the clinical symptoms can not be understood only on the bases of molecular properties of the mutant enzyme. Different (environmental, metabolic, genetic and/or epigenetic) intervening factors can contribute toward the expression of PGK deficient clinical phenotypes.

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Section: Discussionmentioning

confidence: 99%

Molecular Insights on Pathogenic Effects of Mutations Causing Phosphoglycerate Kinase Deficiency

et al. 2012

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“…Recently, homozygous stop codon mutations in muscle glycogen synthase 1 gene ( GYS1 ) were reported to result in profound glycogen deficiency in the heart and skeletal muscle and, consequently, cardiomyopathy and exercise intolerance in siblings aged 10 and 11 years of age (153). In addition, mutations in several genes encoding components of the glycolysis pathway, such as muscle phophofructokinase ( PFKM ) (291, 336, 358), phosphoglycerate kinase 1 ( PGK1 ) (109, 220, 315, 341) and phosphoglycerate mutase 2 ( PGAM2 ) (107, 335, 340), enolase 3 ( ENO3 ) (64), and lactate dehydrogenase A ( LDHA ) (177, 337), have been reported in patients with exercise intolerance.…”

Section: Genetics Cardiorespiratory Endurance and Muscle Strengthmentioning

confidence: 99%

Genomics and Genetics in the Biology of Adaptation to Exercise

Bouchard¹,

Rankinen²,

Timmons³

2011

Comprehensive Physiology

158

132

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This chapter is devoted to the role of genetic variation and gene-exercise interactions in the biology of adaptation to exercise. There is evidence from genetic epidemiology research that DNA sequence differences contribute to human variation in physical activity level, cardiorespiratory fitness in the untrained state, cardiovascular and metabolic response to acute exercise, and responsiveness to regular exercise. Methodological and technological advances have made it possible to undertake the molecular dissection of the genetic component of complex, multifactorial traits, such as those of interest to exercise biology, in terms of tissue expression profile, genes, and allelic variants. The evidence from animal models and human studies is considered. Data on candidate genes, genome-wide linkage results, genome-wide association findings, expression arrays, and combinations of these approaches are reviewed. Combining transcriptomic and genomic technologies has been shown to be more powerful as evidenced by the development of a recent molecular predictor of the ability to increase VO2max with exercise training. For exercise as a behavior and physiological fitness as a state to be major players in public health policies will require that that the role of human individuality and the influence of DNA sequence differences be understood. Likewise, progress in the use of exercise in therapeutic medicine will depend to a large extent on our ability to identify the favorable responders for given physiological properties to a given exercise regimen.

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“…40 Most of these mutations are missense mutants of which one, in addition to encoding a nonconserved Glu252Ala substitution, resulted in aberrant splicing with a consequent 90% reduction in mRNA levels. 69 …”

Section: Phosphoglycerate Kinasementioning

confidence: 99%

The energy-less red blood cell is lost: erythrocyte enzyme abnormalities of glycolysis

Wijk

Solinge

2005

Blood

274

227

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The red blood cell depends solely on the anaerobic conversion of glucose by the Embden-Meyerhof pathway for the generation and storage of high-energy phosphates, which is necessary for the maintenance of a number of vital functions. Many red blood cell enzymopathies have been described that disturb the erythrocyte's integrity, shorten its cellular survival, and result in hemolytic anemia. By far the majority of these enzymopathies are hereditary in nature. In this review, we summarize the current knowledge regarding the genetic, biochemical, and struc- IntroductionThe moment the mature red blood cell leaves the bone marrow, it is optimally adapted to perform the binding and transport of oxygen and its delivery to all tissues. This is the most important task of the erythrocyte during its estimated 120-day journey in the bloodstream. The membrane, hemoglobin, and proteins involved in metabolic pathways of the red blood cell interact to modulate oxygen transport, protect hemoglobin from oxidant-induced damage, and maintain the osmotic environment of the cell. The biconcave shape of the red blood cell provides an optimal area for respiratory exchange. The latter requires passage through microcapillaries, which is achieved by a drastic modification of its biconcave shape, made possible only by the loss of the nucleus and cytoplasmic organelles and, consequently, the ability to synthesize proteins. 1 During their intravascular lifespan, erythrocytes require energy to maintain a number of vital cell functions. These include (1) maintenance of glycolysis; (2) maintenance of the electrolyte gradient between plasma and red cell cytoplasm through the activity of adenosine triphosphate (ATP)-driven membrane pumps; (3) synthesis of glutathione and other metabolites; (4) purine and pyrimidine metabolism; (5) maintenance of hemoglobin's iron in its functional, reduced, ferrous state; (6) protection of metabolic enzymes, hemoglobin, and membrane proteins from oxidative denaturation; and (7) preservation of membrane phospholipid asymmetry. Because of the lack of nuclei and mitochondria, mature red blood cells are incapable of generating energy via the (oxidative) Krebs cycle. Instead, erythrocytes depend on the anaerobic conversion of glucose by the Embden-Meyerhof pathway for the generation and storage of high-energy phosphates (Figure 1). Moreover, erythrocytes possess a unique glycolytic bypass for the production of 2,3-bisphosphoglycerate (2,3-DPG), the RapoportLuebering shunt. This shunt bypasses the phosphoglycerate kinase (PGK) step and accounts for the synthesis and regulation of 2,3-DPG levels that decrease hemoglobin's affinity for oxygen. 2 In addition, 2,3-DPG constitutes an energy buffer.A number of red blood cell enzymopathies have been described in the Embden-Meyerhof pathway. [3][4][5][6] The lack of characteristic changes in red blood cell morphology differentiates the glycolytic enzymopathies from erythrocyte membrane defects and most hemoglobinopathies. In general, red blood cell enzymopathies cause chronic n...

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Retarded and Aberrant Splicings Caused by Single Exon Mutation in a Phosphoglycerate Kinase Variant

Cited by 26 publications

References 0 publications

Molecular Insights on Pathogenic Effects of Mutations Causing Phosphoglycerate Kinase Deficiency

Molecular Insights on Pathogenic Effects of Mutations Causing Phosphoglycerate Kinase Deficiency

Genomics and Genetics in the Biology of Adaptation to Exercise

The energy-less red blood cell is lost: erythrocyte enzyme abnormalities of glycolysis

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