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NPRL2 gene
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Gene

NPRL2 gene

The NPRL2 gene encodes a protein component of the GATOR1 complex, which is essential for regulating the mTOR signaling pathway in cells.

Normal Function

The NPRL2 gene provides instructions for making a protein that is part of a larger protein group (a complex) called GATOR1. This complex is made up of the NPRL2 protein and proteins made from two other genes: DEPDC5 and NPRL3. GATOR1 is found in cells throughout the body, where it regulates a signaling pathway called the mTOR pathway. The mTOR pathway is involved in cell growth and division (proliferation) and the creation (synthesis) of new proteins. In the brain, the mTOR pathway regulates many processes, including the growth and development of nerve cells and their ability to change and adapt over time (plasticity).

The role of the GATOR1 complex is to block this pathway by stopping (inhibiting) the activity of a complex called mTOR complex 1 (mTORC1) that is integral to the mTOR pathway.

Health Conditions Related to Genetic Changes

Autosomal dominant sleep-related hypermotor epilepsy

Genetic changes that cause disease or that increase the risk of disease are sometimes called mutations or pathogenic variants. Pathogenic variants in the NPRL2 gene can cause autosomal dominant sleep-related hypermotor epilepsy (ADSHE), a genetic form of epilepsy that is characterized by seizures that typically begin while a person is sleeping and involve some degree of muscle (motor) activity. The seizures may include repetitive, abnormal muscle movements; muscle stiffness; or abnormal body positioning.

Pathogenic variants in the NPRL2 gene can cause cells to produce an altered version of the NPRL2 protein that disrupts the inhibitory function of the GATOR1 complex. The impaired GATOR1 complex is unable to properly regulate mTORC1, which leads to an overactive mTOR signaling pathway. This overactivation can lead to the seizures in people with ADSHE.

Familial focal epilepsy with variable foci

Pathogenic variants in the NPRL2 gene can also cause familial focal epilepsy with variable foci (FFEVF), an uncommon form of epilepsy that runs in families. Most of these variants lead to the production of an abnormally short version of the NPRL2 protein that does not function properly. Without enough functional NPRL2 protein, GATOR1 cannot effectively regulate mTORC1. Research suggests that increased mTOR pathway signaling in the brain changes the connections between nerve cells (synapses) and increases nerve cell activation (excitation), which can lead to seizures.

Other Names for This Gene

  • nitrogen permease regulator-like 2 (S. cerevisiae)
  • NPR2
  • NPR2-like protein, GATOR1 complex subunit
  • NPR2L
  • tumor suppressor candidate 4
  • TUSC4

Frequently Asked Questions

Pathogenic variants in the NPRL2 gene often lead to the production of an altered or truncated protein that disrupts the structural integrity of the GATOR1 complex. Since GATOR1 is responsible for inhibiting mTORC1, this disruption removes the normal "brake" on the mTOR signaling pathway. The resulting overactivity of mTOR signaling in the brain affects neuronal development and plasticity, leading to the hyperexcitability that manifests as seizures, particularly during sleep.
NPRL2-related epilepsy follows an autosomal dominant inheritance pattern, meaning that a single copy of the mutated gene is sufficient to cause the condition. If a parent has the mutation, there is a 50 percent chance of passing it to each child. Genetic counseling is recommended for families to discuss the risks, the possibility of prenatal or preimplantation genetic testing, and the variable expressivity of the condition, as severity can differ even among family members with the same mutation.
Seizures caused by NPRL2 mutations are typically hypermotor, meaning they involve significant motor activity. They most commonly occur during sleep and may present as repetitive, stereotyped movements, muscle stiffness (tonic posturing), or abnormal body positioning. These seizures can be brief but frequent, and they may be accompanied by autonomic symptoms such as changes in heart rate or breathing, though the motor component is the hallmark feature.
Yes, identifying an NPRL2 mutation can shift the treatment strategy toward mTOR inhibitors, such as everolimus, which target the underlying molecular defect. While standard anti-seizure medications may still be used, mTOR inhibitors have shown efficacy in reducing seizure burden in this specific genetic subtype. Neurologists often consider this targeted therapy when seizures are difficult to control with conventional drugs, aiming to address the root cause of the neuronal hyperexcitability.
Source: MedlinePlus, National Library of Medicine

MedlinePlus brings together authoritative health information from the National Library of Medicine (NLM), the National Institutes of Health (NIH), and other government agencies and health-related organizations.

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