Prevalence of pyruvate kinase deficiency: A systematic literature review

Secrest, Matthew H.; Storm, Mike; Carrington, Courtney; Casso, Deborah; Gilroy, Keely; Pladson, Leanne; Boscoe, Audra

doi:10.1111/ejh.13424

Cited by 44 publications

(36 citation statements)

References 39 publications

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“… 63-65 The causes of this variability can be explained by the rarity of the disorder, the high percentage of undiagnosed cases and the absence of disease registries and specific population studies. 65 …”

Section: Geographical Distribution Of Pklr Variantmentioning

confidence: 99%

Molecular heterogeneity of pyruvate kinase deficiency

Bianchi

Fermo

2020

haematol

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Red cell pyruvate kinase (PK) deficiency is the most common glycolytic defect associated with congenital non-spherocytic hemolytic anemia. The disease, transmitted as an autosomal recessive trait, is caused by mutations in the PKLR gene and is characterized by molecular and clinical heterogeneity; anemia ranges from mild or fully compensated hemolysis to life-threatening forms necessitating neonatal exchange transfusions and/or subsequent regular transfusion support; complications include gallstones, pulmonary hypertension, extramedullary hematopoiesis and iron overload. Since identification of the first pathogenic variants responsible for PK deficiency in 1991, more than 300 different variants have been reported, and the study of molecular mechanisms and the existence of genotype-phenotype correlations have been investigated in-depth. In recent years, during which progress in genetic analysis, next-generation sequencing technologies and personalized medicine have opened up important landscapes for diagnosis and study of molecular mechanisms of congenital hemolytic anemias, genotyping has become a prerequisite for accessing new treatments and for evaluating disease state and progression. This review examines the extensive molecular heterogeneity of PK deficiency, focusing on the diagnostic impact of genotypes and new acquisitions on pathogenic non-canonical variants. The recent progress and the weakness in understanding the genotype-phenotype correlation, and its practical usefulness in light of new therapeutic opportunities for PK deficiency are also discussed.

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Section: Geographical Distribution Of Pklr Variantmentioning

confidence: 99%

Molecular heterogeneity of pyruvate kinase deficiency

Bianchi

Fermo

2020

haematol

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“…As an example, nonspherocytic hemolytic anemia is caused by a range of point mutations in the pyruvate kinase isozyme that is expressed in erythrocytes (RPYK). A database of 215 disease-causing mutations has been assembled by several groups (Pendergrass et al 2006;Secrest et al 2020;Canu et al 2016). We assume that these mutations either greatly reduced or abolished enzyme function.…”

Section: Rheostat Positions Might Be Identified By Comparing Disease mentioning

confidence: 99%

Rheostat positions: A new classification of protein positions relevant to pharmacogenomics

et al. 2020

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To achieve the full potential of pharmacogenomics, one must accurately predict the functional outcomes that arise from amino acid substitutions in proteins. Classically, researchers have focused on understanding the consequences of individual substitutions. However, literature surveys have shown that most substitutions were created at evolutionarily conserved positions. Awareness of this bias leads to a shift in perspective, from considering the outcomes of individual substitutions to understanding the roles of individual protein positions. Conserved positions tend to act as "toggle" switches, with most substitutions abolishing function. However, nonconserved positions have been found equally capable of affecting protein function. Indeed, many nonconserved positions act like functional dimmer switches ("rheostat" positions): this is revealed when multiple substitutions are made at a single position. Each substitution has a different functional outcome; the set of substitutions spans a range of outcomes. Finally, some nonconserved positions appear neutral, capable of accommodating all amino acid types without modifying function. This paper reviews the currently-known properties of rheostat positions, with examples shown for pyruvate kinase, organic anion transporting polypeptide 1B1, the beta-lactamase inhibitory protein, and angiotensin-converting enzyme 2. Outcomes observed for rheostat positions have implications for the rational design of drug analogs and allosteric drugs. Furthermore, this new framework-comprising three types of protein positions-provides a new approach to interpreting disease and population-based databases of amino acid changes. In conclusion, although a full understanding of substitution outcomes at rheostat positions poses a challenge, utilization of this new frame of reference will further advance the application of pharmacogenomics.

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“…These isoforms share similar features, where they catalyze the final step in glycolysis and exhibit the same primary structure containing four major domains: A, B, C, and N [ 31 , 32 , 33 , 34 ]. However, the PK isoforms differ in their enzymatic potential, allosteric regulation [ 35 ], amino acid sequence, tissue distribution [ 14 , 36 ], and contribution to health and disease [ 37 , 38 ]. PKM1 and PKM2 are both expressed from the PKM gene and conversed across vertebrates [ 39 ].…”

Section: Pkm2: Uncovering the Originmentioning

confidence: 99%

The Role of PKM2 in Metabolic Reprogramming: Insights into the Regulatory Roles of Non-Coding RNAs

Puckett

Alquraishi

Chowanadisai

et al. 2021

IJMS

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Pyruvate kinase is a key regulator in glycolysis through the conversion of phosphoenolpyruvate (PEP) into pyruvate. Pyruvate kinase exists in various isoforms that can exhibit diverse biological functions and outcomes. The pyruvate kinase isoenzyme type M2 (PKM2) controls cell progression and survival through the regulation of key signaling pathways. In cancer cells, the dimer form of PKM2 predominates and plays an integral role in cancer metabolism. This predominance of the inactive dimeric form promotes the accumulation of phosphometabolites, allowing cancer cells to engage in high levels of synthetic processing to enhance their proliferative capacity. PKM2 has been recognized for its role in regulating gene expression and transcription factors critical for health and disease. This role enables PKM2 to exert profound regulatory effects that promote cancer cell metabolism, proliferation, and migration. In addition to its role in cancer, PKM2 regulates aspects essential to cellular homeostasis in non-cancer tissues and, in some cases, promotes tissue-specific pathways in health and diseases. In pursuit of understanding the diverse tissue-specific roles of PKM2, investigations targeting tissues such as the kidney, liver, adipose, and pancreas have been conducted. Findings from these studies enhance our understanding of PKM2 functions in various diseases beyond cancer. Therefore, there is substantial interest in PKM2 modulation as a potential therapeutic target for the treatment of multiple conditions. Indeed, a vast plethora of research has focused on identifying therapeutic strategies for targeting PKM2. Recently, targeting PKM2 through its regulatory microRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) has gathered increasing interest. Thus, the goal of this review is to highlight recent advancements in PKM2 research, with a focus on PKM2 regulatory microRNAs and lncRNAs and their subsequent physiological significance.

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Prevalence of pyruvate kinase deficiency: A systematic literature review

Cited by 44 publications

References 39 publications

Molecular heterogeneity of pyruvate kinase deficiency

Molecular heterogeneity of pyruvate kinase deficiency

Rheostat positions: A new classification of protein positions relevant to pharmacogenomics

The Role of PKM2 in Metabolic Reprogramming: Insights into the Regulatory Roles of Non-Coding RNAs

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