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PKLR
pyruvate kinase L/R
The PKLR gene encodes the pyruvate kinase enzyme, crucial for the final stage of glycolysis, the metabolic pathway that generates energy within red blood cells and the liver. The PKLR gene provides instructions for making the pyruvate kinase enzyme, which plays a vital role in glucose metabolism.
PKLR is located on the long (q) arm of chromosome 1, at band 1q22. Arm ratio per GRCh38 - banding schematic.
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Overview
The PKLR gene, also known as pyruvate kinase L/R, is essential for metabolic processes in the human body, particularly within red blood cells and the liver. It provides the genetic blueprint for synthesising the pyruvate kinase enzyme, a key player in energy production. Understanding PKLR is important for diagnosing and managing inherited metabolic disorders, such as pyruvate kinase deficiency.
What the gene does
The PKLR gene directs the production of the pyruvate kinase enzyme, which is critical for glycolysis, a fundamental energy-generating pathway. This enzyme facilitates the final step of glycolysis, converting phosphoenolpyruvate (PEP) into pyruvate and adenosine triphosphate (ATP). ATP serves as the primary energy currency for cellular functions. The pyruvate kinase enzyme is highly expressed in red blood cells and liver cells, where it ensures a steady supply of energy needed for their specialised functions. In red blood cells, this energy is vital for maintaining cell shape and integrity.
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Chromosome location
The PKLR gene is situated on chromosome 1, specifically at band 1q22. This location refers to the long (q) arm of chromosome 1. The precise positioning of PKLR on the human genome is important for genetic mapping and understanding its relationship to other genes.
Protein structure
The PKLR gene codes for a protein consisting of 574 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the PKLR gene can alter the function of the pyruvate kinase enzyme, leading to various health implications. Over 200 distinct genetic changes in PKLR have been identified in individuals with associated conditions. These variants typically involve single amino acid changes or result in truncated proteins, which can significantly reduce enzyme activity.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1022G>C | p.Gly341Ala | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate kinase deficiency of red cells |
c.1462C>T | p.Arg488Ter | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.1484C>T | p.Ala495Val | Pathogenic | ★★☆☆ | not provided |
c.1501C>T | p.Gln501Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1542dup | p.Leu516fs | Pathogenic | ★★☆☆ | not provided |
c.625_637del | p.Arg209fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.628_629del | p.Val210fs | Pathogenic | ★★☆☆ | not provided |
c.694+2T>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Pyruvate kinase deficiency of red cells |
c.808C>T | p.Arg270Ter | Pathogenic | ★★☆☆ | Pyruvate kinase deficiency of red cells |
c.994_1003dup | p.Val335fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the PKLR gene are primarily associated with an inherited condition known as pyruvate kinase deficiency. This autosomal recessive disorder affects red blood cells, leading to a type of chronic anaemia. Individuals with pyruvate kinase deficiency typically inherit two altered copies of the PKLR gene, one from each parent. Some research also suggests that individuals carrying one copy of a PKLR variant may have partial protection against malaria, due to reduced parasite invasion of red blood cells.
- Pyruvate kinase deficiency Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic PKLR variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The PKLR gene is included in several NHS Genomic Medicine Service national test panels. These panels cover conditions such as Cytopenias and congenital anaemias, Foetal anomalies, Foetal hydrops, and Rare anaemia, indicating its recognised clinical importance within the UK healthcare system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main role of the PKLR gene?
The PKLR gene provides instructions for making the pyruvate kinase enzyme, which is crucial for the final step of glycolysis, a process that generates energy in red blood cells and the liver.
What condition is associated with PKLR gene variants?
Variants in the PKLR gene are primarily associated with pyruvate kinase deficiency, an inherited disorder that affects red blood cells and can cause chronic anaemia.
How is pyruvate kinase deficiency inherited?
Pyruvate kinase deficiency is inherited in an autosomal recessive manner, meaning an individual must inherit two altered copies of the PKLR gene, one from each parent, to develop the condition.
References
- Rider NL, Strauss KA, Brown K. Erythrocyte pyruvate kinase deficiency in an old-order Amish cohort: longitudinal risk and disease management. American journal of hematology. 2011. PMID: 21815188
- van Wijk R, Huizinga EG, van Wesel AC. Fifteen novel mutations in PKLR associated with pyruvate kinase (PK) deficiency: structural implications of amino acid substitutions in PK. Human mutation. 2009. PMID: 19085939
- Climent F, Roset F, Repiso A. Red cell glycolytic enzyme disorders caused by mutations: an update. Cardiovascular & hematological disorders drug targets. 2009. PMID: 19519368
- Ayi K, Min-Oo G, Serghides L. Pyruvate kinase deficiency and malaria. The New England journal of medicine. 2008. PMID: 18420493
- Durand PM, Coetzer TL. Pyruvate kinase deficiency protects against malaria in humans. Haematologica. 2008. PMID: 18460648
- Zanella A, Fermo E, Bianchi P. Pyruvate kinase deficiency: the genotype-phenotype association. Blood reviews. 2007. PMID: 17360088
- Zanella A, Fermo E, Bianchi P. Red cell pyruvate kinase deficiency: molecular and clinical aspects. British journal of haematology. 2005. PMID: 15982340
- van Wijk R, van Solinge WW. The energy-less red blood cell is lost: erythrocyte enzyme abnormalities of glycolysis. Blood. 2005. PMID: 16051738
- Beutler E, Gelbart T. Estimating the prevalence of pyruvate kinase deficiency from the gene frequency in the general white population. Blood. 2000. PMID: 10828047