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PKLR
pyruvate kinase L/R
The PKLR gene provides instructions for creating the pyruvate kinase enzyme, which plays a vital role in glucose metabolism and energy production, particularly in red blood cells and the liver. The PKLR gene encodes the pyruvate kinase L/R enzyme, essential for the final step of glycolysis, a key energy-producing pathway.
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, or pyruvate kinase L/R, is crucial for cellular energy production. It provides the genetic blueprint for the pyruvate kinase enzyme, which is predominantly active in the liver and red blood cells. This enzyme facilitates a critical step in glycolysis, the metabolic pathway that breaks down glucose to generate energy for cellular processes.
Mutations in the PKLR gene are linked to inherited conditions, most notably pyruvate kinase deficiency. This condition primarily affects red blood cells, leading to their premature breakdown and a type of anaemia.
What the gene does
The PKLR gene provides instructions for synthesising the pyruvate kinase enzyme, a central component of glycolysis. Glycolysis is a fundamental metabolic process where glucose, a simple sugar, is broken down to produce energy in the form of adenosine triphosphate (ATP).
Specifically, the pyruvate kinase enzyme catalyses the final step of the glycolytic pathway. In this reaction, a phosphate group is transferred from phosphoenolpyruvate to adenosine diphosphate (ADP), resulting in the formation of pyruvate and ATP. ATP serves as the primary energy currency for cells, powering various cellular functions. In red blood cells, this energy is vital for maintaining cell integrity and proper function.
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Chromosome location
The PKLR gene is located on chromosome 1, specifically at position 1q22. This region denotes its precise band on the long arm of chromosome 1. The gene spans a significant length, containing several exons that are transcribed and translated into the pyruvate kinase protein.
Protein structure
The pyruvate kinase protein encoded by the PKLR gene consists of 574 amino acids. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Genetic variations within the PKLR gene can alter the function or production of the pyruvate kinase enzyme. Over 200 distinct mutations have been identified in individuals with conditions associated with this gene. These genetic changes often lead to a reduction in enzyme activity or result in an abnormally shortened protein, impacting its ability to carry out its metabolic role effectively.
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.1116+2T>G | - | Pathogenic | ★★☆☆ | PKLR-related disorder |
c.1179T>A | p.Asn393Lys | Pathogenic/Likely pathogenic | ★★☆☆ | PKLR-related disorder |
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.1574G>A | p.Trp525Ter | Pathogenic/Likely pathogenic | ★★☆☆ | PKLR-related disorder |
c.625_637del | p.Arg209fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.628_629del | p.Val210fs | 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 autosomal recessive inherited condition known as pyruvate kinase deficiency. Individuals with this disorder typically inherit two altered copies of the gene, one from each parent. This deficiency leads to a shortage of functional pyruvate kinase enzyme, particularly in red blood cells. This can result in the premature destruction of red blood cells, causing chronic haemolytic anaemia.
- 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 England Genomic Medicine Service approved panels. It is listed as 'green' on panels for Cytopenias and congenital anaemias, Foetal anomalies (R21), Foetal hydrops, and Rare anaemia (R92), indicating that variants in this gene are considered to have a strong evidence base for pathogenicity in these contexts.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the PKLR gene?
The PKLR gene provides instructions for the pyruvate kinase enzyme, which is crucial for the final step of glycolysis, a metabolic pathway that generates energy from glucose in the liver and red blood cells.
What condition is associated with variants in the PKLR gene?
Variants in the PKLR gene are primarily associated with pyruvate kinase deficiency, an autosomal recessive disorder that leads to chronic haemolytic anaemia due to the premature destruction of red blood cells.
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