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NPRL2 gene
URL of this page: https://medlineplus.gov/genetics/gene/nprl2/

NPRL2 gene

NPR2 like, GATOR1 complex subunit

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.

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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.

More About This Health Condition

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

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases

References

  • Baldassari S, Licchetta L, Tinuper P, Bisulli F, Pippucci T. GATOR1 complex: the common genetic actor in focal epilepsies. J Med Genet. 2016 Aug;53(8):503-10. doi: 10.1136/jmedgenet-2016-103883. Epub 2016 May 19. Citation on PubMed
  • Baulac S. mTOR signaling pathway genes in focal epilepsies. Prog Brain Res. 2016;226:61-79. doi: 10.1016/bs.pbr.2016.04.013. Epub 2016 Jun 7. Citation on PubMed
  • Dibbens LM, de Vries B, Donatello S, Heron SE, Hodgson BL, Chintawar S, Crompton DE, Hughes JN, Bellows ST, Klein KM, Callenbach PM, Corbett MA, Gardner AE, Kivity S, Iona X, Regan BM, Weller CM, Crimmins D, O'Brien TJ, Guerrero-Lopez R, Mulley JC, Dubeau F, Licchetta L, Bisulli F, Cossette P, Thomas PQ, Gecz J, Serratosa J, Brouwer OF, Andermann F, Andermann E, van den Maagdenberg AM, Pandolfo M, Berkovic SF, Scheffer IE. Mutations in DEPDC5 cause familial focal epilepsy with variable foci. Nat Genet. 2013 May;45(5):546-51. doi: 10.1038/ng.2599. Epub 2013 Mar 31. Citation on PubMed
  • Kurahashi H, Hirose S. Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy. 2002 May 16 [updated 2023 Mar 23]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from http://www.ncbi.nlm.nih.gov/books/NBK1169/ Citation on PubMed
  • Licchetta L, Pippucci T, Baldassari S, Minardi R, Provini F, Mostacci B, Plazzi G, Tinuper P, Bisulli F; Collaborative Group of Italian League Against Epilepsy (LICE) Genetic Study Group on SHE. Sleep-related hypermotor epilepsy (SHE): Contribution of known genes in 103 patients. Seizure. 2020 Jan;74:60-64. doi: 10.1016/j.seizure.2019.11.009. Epub 2019 Nov 23. Citation on PubMed
  • Weckhuysen S, Marsan E, Lambrecq V, Marchal C, Morin-Brureau M, An-Gourfinkel I, Baulac M, Fohlen M, Kallay Zetchi C, Seeck M, de la Grange P, Dermaut B, Meurs A, Thomas P, Chassoux F, Leguern E, Picard F, Baulac S. Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia. Epilepsia. 2016 Jun;57(6):994-1003. doi: 10.1111/epi.13391. Epub 2016 May 13. Citation on PubMed

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