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POLG
DNA polymerase gamma, catalytic subunit
The POLG gene provides instructions for DNA polymerase gamma, an enzyme essential for replicating and repairing mitochondrial DNA, with variants linked to a spectrum of mitochondrial disorders. The POLG gene encodes the catalytic subunit of DNA polymerase gamma (pol γ), the sole DNA polymerase responsible for maintaining the mitochondrial genome.
POLG is located on the long (q) arm of chromosome 15, at band 15q26.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The POLG gene is responsible for producing the catalytic alpha subunit of DNA polymerase gamma (pol γ), an enzyme critical for the health and function of mitochondria. Mitochondria are vital cellular components that generate most of the chemical energy needed for biochemical reactions within the cell.
Dysfunction of the POLG gene can lead to a group of conditions known as POLG-related disorders. These are typically characterised by a variety of symptoms affecting multiple organ systems, particularly the brain, nerves, and muscles.
What the gene does
The POLG gene provides the blueprint for the alpha subunit of DNA polymerase gamma (pol γ), an enzyme exclusively found in mitochondria. This enzyme is crucial for the replication and repair of mitochondrial DNA (mtDNA), which carries essential genetic information for mitochondrial function. Pol γ operates by 'reading' existing DNA sequences and synthesising new DNA strands based on these templates, ensuring the integrity and proper copying of the mitochondrial genome.
Effective functioning of pol γ relies on its catalytic alpha subunit, encoded by POLG, associating with two copies of a beta subunit. This complete enzyme complex is vital for the process of oxidative phosphorylation, where energy from food is converted into a usable form for the cell. Impaired pol γ activity, often due to POLG variants, can lead to reduced mtDNA replication and accumulation of mtDNA damage, disrupting mitochondrial energy production.
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Chromosome location
The POLG gene is situated on chromosome 15 at position 15q26.1. This specific location refers to the long (q) arm of chromosome 15, within region 26, band 1. The gene spans a significant length of DNA, providing instructions for a protein of 1239 amino acids.
Protein structure
The POLG protein, with 1239 amino acids, exhibits a complex domain organisation crucial for its enzymatic activity. Several disordered regions are present, including one spanning amino acids 1-68 and another from 318-340, as well as 506-531. A specific region from amino acids 43-55 is noted as not contributing to polymerase and exonuclease enzymatic activities. Key exonuclease motifs include Exo I (196-200), Exo II (267-275), and Exo III (395-403). The protein also features an Accessory-interacting determinant from amino acids 510-571. Catalytic polymerase activity is linked to motifs Pol A (887-896), Pol B (943-958), and Pol C (1134-1141), along with a Trigger loop found between amino acids 858-864.
Key variants
Variants within the POLG gene can alter the structure or function of the DNA polymerase gamma enzyme. These genetic changes can range from single amino acid substitutions to larger deletions or insertions, impacting the enzyme's ability to replicate and repair mitochondrial DNA. The consequence of such variants is typically reduced enzymatic activity, leading to mitochondrial dysfunction.
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.1180C>T | p.Gln394Ter | Pathogenic | ★★☆☆ | Progressive sclerosing poliodystrophy |
c.1185C>G | p.Tyr395Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Progressive sclerosing poliodystrophy |
c.1251-2A>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Progressive sclerosing poliodystrophy |
c.1293del | p.Val432fs | Pathogenic/Likely pathogenic | ★★☆☆ | Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 1 |
c.1356T>G | p.Tyr452Ter | Pathogenic | ★★☆☆ | Mitochondrial DNA depletion syndrome 4b |
c.2420G>C | p.Arg807Pro | Pathogenic/Likely pathogenic | ★★☆☆ | Progressive sclerosing poliodystrophy |
c.2421dup | p.Ile808fs | Pathogenic | ★★☆☆ | Progressive sclerosing poliodystrophy |
c.2480+1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | POLG-related disorder |
c.2690G>A | p.Trp897Ter | Pathogenic | ★★☆☆ | POLG-related disorder |
c.2739C>A | p.Cys913Ter | Pathogenic | ★★☆☆ | Progressive sclerosing poliodystrophy |
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 POLG gene are associated with a spectrum of inherited disorders known as POLG-related disorders, which typically follow an autosomal recessive inheritance pattern. These conditions often present with neurological symptoms and can include Chronic progressive external ophthalmoplegia (Mitochondrial). Other manifestations can include Alpers-Huttenlocher syndrome, characterised by seizures and developmental regression, and ataxia neuropathy spectrum, involving coordination and nerve function issues. Childhood myocerebrohepatopathy syndrome (MCHS) also falls under POLG-related disorders, affecting muscles, brain, and liver function.
Inheritance pattern
Conditions caused by pathogenic POLG 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 POLG gene is extensively assessed within the NHS Genomic Medicine Service, being listed on numerous Green R number panels in PanelApp UK. This widespread inclusion underscores its significance in diagnosing a broad range of conditions. Notably, POLG is part of panels for 'Acute rhabdomyolysis', 'Ataxia and cerebellar anomalies - childhood onset', 'Mitochondrial disorders', 'POLG-related disorder (R315)', 'Hereditary ataxia', and 'Inherited white matter disorders', among others, reflecting its role in diverse neurological and metabolic pathologies.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the POLG gene?
The POLG gene provides instructions for the catalytic subunit of DNA polymerase gamma, the only enzyme responsible for replicating and repairing mitochondrial DNA. This function is essential for normal mitochondrial energy production and cellular health.
What kind of health problems are associated with POLG gene variants?
Variants in the POLG gene are linked to a group of conditions called POLG-related disorders. These conditions commonly affect the brain, nerves, and muscles, leading to symptoms like seizures, coordination problems (ataxia), muscle weakness, and liver dysfunction.
How are POLG-related disorders inherited?
POLG-related disorders are typically inherited in an autosomal recessive pattern. This means an individual must inherit two altered copies of the POLG gene, one from each parent, to develop the condition. Carriers of a single altered copy generally do not show symptoms.
References
- Sohl CD, Kasiviswanathan R, Copeland WC. Mutations in human DNA polymerase γ confer unique mechanisms of catalytic deficiency that mirror the disease severity in mitochondrial disorder patients. Human molecular genetics. 2013. PMID: 23208208
- Stumpf JD, Copeland WC. Mitochondrial DNA replication and disease: insights from DNA polymerase γ mutations. Cellular and molecular life sciences : CMLS. 2011. PMID: 20927567
- Milone M, Massie R. Polymerase gamma 1 mutations: clinical correlations. The neurologist. 2010. PMID: 20220442
- Rocher C, Taanman JW, Pierron D. Influence of mitochondrial DNA level on cellular energy metabolism: implications for mitochondrial diseases. Journal of bioenergetics and biomembranes. 2008. PMID: 18415670
- Yu Wai Man CY, Chinnery PF, Griffiths PG. Extraocular muscles have fundamentally distinct properties that make them selectively vulnerable to certain disorders. Neuromuscular disorders : NMD. 2005. PMID: 15639116
- Chan SS, Longley MJ, Copeland WC. The common A467T mutation in the human mitochondrial DNA polymerase (POLG) compromises catalytic efficiency and interaction with the accessory subunit. The Journal of biological chemistry. 2005. PMID: 16024923
- Van Goethem G, Martin JJ, Dermaut B. Recessive POLG mutations presenting with sensory and ataxic neuropathy in compound heterozygote patients with progressive external ophthalmoplegia. Neuromuscular disorders : NMD. 2003. PMID: 12565911
- Van Goethem G, Martin JJ, Van Broeckhoven C. Progressive external ophthalmoplegia characterized by multiple deletions of mitochondrial DNA: unraveling the pathogenesis of human mitochondrial DNA instability and the initiation of a genetic classification. Neuromolecular medicine. 2003. PMID: 12835509
- Van Goethem G, Dermaut B, Löfgren A. Mutation of POLG is associated with progressive external ophthalmoplegia characterized by mtDNA deletions. Nature genetics. 2001. PMID: 11431686
- Moraes CT, Shanske S, Tritschler HJ. mtDNA depletion with variable tissue expression: a novel genetic abnormality in mitochondrial diseases. American journal of human genetics. 1991. PMID: 1998336