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NPRL3 gene
Reviewed by Medicinsk Expert•Last updated: 2026-10-22•Gene

NPRL3 gene

The NPRL3 gene provides instructions for a protein that forms part of the GATOR1 complex, which regulates the mTOR pathway to control cell growth and division.

Normal Function

The NPRL3 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 NPRL3 protein and proteins made from two other genes: DEPDC5 and NPRL2. 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

MedlinePlus Genetics provides information about Autosomal dominant sleep-related hypermotor epilepsy.

Familial focal epilepsy with variable foci

Variants (also called mutations) in the NPRL3 gene can cause familial focal epilepsy with variable foci (FFEVF), an uncommon form of recurrent seizures (epilepsy) that runs in families. Most of these variants lead to the production of an abnormally short protein that does not function properly. A reduced amount of functional GATOR1 leads to overactivity of mTORC1 and excessive signaling of the mTOR pathway. 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

  • C16orf35
  • CGTHBA
  • chromosome 16 open reading frame 35
  • HS-40
  • MARE
  • nitrogen permease regulator-like 3 (S. cerevisiae)
  • NPR3
  • NPR3-like, GATOR1 complex subunit
  • RMD11

Frequently Asked Questions

While both conditions are linked to NPRL3 variants and involve mTOR pathway dysregulation, ADSHE is characterized by seizures that predominantly occur during sleep and feature prominent motor symptoms like repetitive movements or stiffness. FFEVF is a broader classification for familial focal epilepsy where seizure foci can vary; NPRL3 variants are a specific genetic cause within this spectrum. In practice, many patients previously diagnosed with FFEVF due to NPRL3 mutations are now reclassified under the ADSHE framework if their seizure semiology matches the sleep-related hypermotor profile.
Mutations in the NPRL3 gene typically result in a shorter, non-functional protein that disrupts the GATOR1 complex. This complex normally acts as a brake on the mTOR signaling pathway. When the brake fails, the mTOR pathway becomes overactive, leading to excessive signaling in the brain. This hyperactivity alters the connections between nerve cells (synapses) and increases neuronal excitability, which lowers the threshold for seizures, particularly during sleep.
Yes, because the underlying mechanism involves mTOR pathway overactivity, mTOR inhibitors such as everolimus are a targeted therapeutic option. Clinical evidence suggests that these medications can reduce seizure frequency in patients with mTOR-related epilepsies, including those with NPRL3 variants. However, treatment must be carefully monitored by a neurologist to manage potential side effects and determine the optimal dosage for each individual.
Genetic testing is generally recommended for children with early-onset sleep-related hypermotor epilepsy, especially if there is a family history of epilepsy or if seizures are resistant to standard anti-seizure medications. Identifying an NPRL3 variant confirms the diagnosis, helps rule out other causes, and may guide treatment decisions toward mTOR-targeted therapies. It also provides important information for genetic counseling regarding the risk of passing the condition to future children.
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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