The POLG gene gives cells the main tool they use to copy and repair mitochondrial DNA, the small set of genes inside the parts of cells that make energy. If the POLG gene does not work properly, tissues with high energy needs, such as the brain, muscles, nerves, and liver, may be affected. This gene plays an important role in keeping cells supplied with energy, so harmful variants can be linked to seizures, muscle weakness, balance problems, vision changes, nerve symptoms, or liver disease.
What is a gene?
Genes are stretches of DNA that hold instructions your cells use to make molecules or manage processes in the body. Some genes provide the information needed to produce proteins, the parts of cells that do much of the work. Other genes mainly control when certain processes happen, where they happen, and how strongly they operate. As a group, genes influence how the body develops and functions, and they can affect how you respond to food, stress, or medications. To go into this topic in more detail, you can learn more in LearnHub.
Overview
POLGGene function
What if the gene works
The POLG gene helps make the main enzyme that copies and repairs mitochondrial DNA, the small set of DNA inside cells’ energy producing parts. This helps cells produce energy and keep tissues like muscle, nerves, and the liver working.
Risk
What if the gene does not work
Variants in the POLG gene can cause mitochondrial disease, affecting the brain, muscles, nerves, and liver. Effects range from milder adult drooping eyelids and weakness to seizures, movement problems, and liver failure that may begin earlier in life.
Treatment
What does that mean for your treatment
Pathogenic variants in the POLG gene strongly affect drug choice: valproate (valproic acid) is generally avoided because it can trigger severe liver failure in people with POLG related disease. Other seizure medicines are usually chosen instead.
Conditions associated with POLG
Gene function
What if the gene works
Your cells need the POLG gene to keep the parts of the cell that make energy supplied with healthy genetic instructions. It helps copy and check mitochondrial DNA, the small set of DNA inside mitochondria. This is a key part of how the POLG gene helps mitochondria support steady energy production in muscles, nerves, and other active tissues.
The POLG gene makes the main enzyme that copies mitochondrial DNA. This allows mitochondria to pass on a full set of instructions as cells grow, divide, and replace older mitochondria.
Its enzyme also proofreads newly copied mitochondrial DNA, which means it checks for copying mistakes and corrects them. This helps keep the DNA sequence accurate over time.
POLG also takes part in repairing mitochondrial DNA during normal wear and tear. By helping restore small areas of damage, it supports the stability of the DNA that mitochondria need for everyday energy production.
What is a variant?
A genetic variant is a minor change in a gene’s DNA sequence. These changes are common and help shape normal human diversity, including differences in appearance, metabolism, and the way the body responds to environmental influences. Many variants do not have any noticeable effect and are simply part of natural genetic variation. In some situations, though, a variant can change how a gene works more significantly and may contribute to, or directly cause, a genetic condition.
Genetic variants
What if the gene does not work
POLG gene variants affect mitochondrial DNA copying by changing the enzyme's shape, stability, or ability to add DNA building blocks accurately. Some variants mildly reduce activity, while more severe variants can greatly disrupt the enzyme or stop it from working, leading to loss or buildup of errors in mitochondrial DNA. This functional spectrum often helps explain why some people develop POLG related disease later and more mildly, while others have earlier or broader symptoms.
How variants are linked to conditions
Disease-causing variants in the POLG gene cause POLG-related mitochondrial disease, a group of inherited conditions that can affect the brain, muscles, nerves, eyes, and liver. Well-established diagnoses include Alpers-Huttenlocher syndrome, progressive external ophthalmoplegia (slowly worsening weakness of eye movements), and ataxia neuropathy spectrum, which often involves poor balance and nerve symptoms. Symptoms and the age they begin vary widely, even within the same family.
A variant is not necessarily a diagnosis
Genetic variants are a usual part of human biology, and they are common in the general population. Most do not have a direct effect on health and instead reflect normal human diversity. For many genes, having a variant associated with a condition suggests a possible link rather than a definite diagnosis, especially when several genes and environmental factors play a role. In some situations, though, a single well characterized variant in a specific gene can be enough to confirm a diagnosis.
Are there things that can increase or change my risk?
For many living with a harmful change in the POLG gene, risk is driven mainly by the genetic change itself. Certain seizure medicines, especially valproate, can sharply raise the risk of severe liver injury, and infections or other body stresses may sometimes bring on symptoms or make them worse. Regular follow-up can help spot problems early and avoid known triggers.
Inheritance of POLG variants
The inheritance of the POLG gene variants depends on the specific POLG-related condition. Many POLG-linked conditions follow an autosomal recessive pattern, which means a child inherits one variant in the POLG gene from each parent, and carrier parents are often unaffected. Some POLG-related conditions are autosomal dominant, so a person carrying one disease-causing variant in the POLG gene can pass it to a child with a 50% chance in each pregnancy. Because both patterns are recognized, family risk depends on the exact variant and diagnosis.
What does my POLG result mean for my family?
POLG results can have different family implications because this gene is linked to both recessive and dominant inherited conditions. In some families, parents and siblings may be healthy carriers, while in others, a parent, child, brother, or sister may also have the same gene change and a chance of related symptoms. The meaning for relatives depends on the exact POLG variant and the condition tied to it.
Genetic information
Genetic testing
How you find out about variants
Genetic testing for POLG variants uses a blood or saliva sample to read the POLG gene and look for changes linked with POLG related conditions. This can show whether you carry a disease causing variant, but the result is interpreted alongside your symptoms and family history because some findings need careful review.
When should I consider getting a genetic test?
Consider testing for the POLG gene if there is a personal or family history of repeated unexplained seizures, muscle weakness, balance problems, drooping eyelids, or liver failure. Testing can also help clarify risk before using valproate, a seizure medicine that can cause severe liver injury in some people with POLG changes.
A genetic result is only one part of your health story
Genetic results can be informative, although what they can tell you varies with the condition and the kind of variant found. Over time, factors like lifestyle, environment, age, and medical history also influence how the body functions. With some conditions, particularly those shaped by many genes, genetic information provides context rather than certainty and makes the most sense when considered alongside other parts of care. In other situations, a genetic result can give a clear answer. In areas such as medication response, these results may help place personal experiences into perspective.
Pharmacogenetics
How variants shape your response to medicine
Genetic variation can affect how people respond to medicines. Two people can take the same treatment and have different results because their bodies absorb, break down, or respond to the drug in different ways. These inherited differences are common and can influence how well a medicine works or how sensitive someone is to side effects. This is one reason medication response can vary from person to person, even when the diagnosis and dose are the same.
What is Pharmacogenetics?
Pharmacogenetics examines how differences in genes affect the way people respond to medications. It studies connections between genes and drugs to help explain why the same treatment may work differently from one person to another. For many medicines, genes can influence how strongly a drug works or how the body handles it. This understanding can support more informed and individualized treatment choices. To explore this subject further, you can learn more in the LearnHub.
Drugs influenced by the POLG gene
When should I seek medical advice?
There is not yet a broadly confirmed role for this gene in guiding everyday medication choices, so general questions about medicines or side effects are best discussed with your doctor. POLG has been linked to a much higher risk of serious liver injury with valproic acid, especially in people with POLG-related mitochondrial conditions, so bring this up before starting or changing that treatment.
History
Across cultures and time periods, inherited patterns were noted in families with unexplained seizures, muscle weakness, and liver problems, long before the cause was clear. In the 1990s, researchers identified the POLG gene and linked it to the enzyme that copies mitochondrial DNA, marking an important step in understanding several mitochondrial conditions. From these first observations, research expanded steadily. Doctors then recognized that changes in the POLG gene could underlie conditions once described separately, including Alpers syndrome and progressive external ophthalmoplegia. As genetic testing improved, the picture became clearer, and POLG became one of the best-known genes in mitochondrial medicine. This history helped connect many puzzling family stories to a shared genetic cause.