NPRL2 – Focal Epilepsy

NPRL2, nitrogen permease regulator-like 2 (HGNC:24969), encodes a core component of the GATOR1 complex, an inhibitor of the mechanistic target of rapamycin complex 1 (mTORC1) signaling. Heterozygous pathogenic variants in NPRL2 have been identified in patients with focal epilepsy, implicating loss of GATOR1-mediated mTORC1 regulation in epileptogenesis (PMID:26505888). Variants in the other GATOR1 subunits, DEPDC5 and NPRL3, produce a similar focal epilepsy phenotype spectrum, supporting NPRL2 as the third key gene in this pathway. Affected individuals often present with drug-resistant seizures and variable electroencephalographic foci. Clinical management decisions, such as avoidance of mTORC1-activating drugs, have been influenced by NPRL2 genetic diagnosis. These findings establish strong clinical validity for NPRL2 in focal epilepsy.

In focal epilepsy cohorts, the inheritance of NPRL2-related disease is autosomal dominant with incomplete penetrance. In a study of 404 unrelated focal epilepsy probands, five individuals harbored heterozygous loss-of-function NPRL2 mutations, including c.100C>T (p.Arg34Ter) and c.640G>C (p.Asp214His) (PMID:26505888). Segregation analysis in two multiplex families demonstrated cosegregation of NPRL2 variants with disease in affected relatives (PMID:26505888). An independent splicing variant, c.339+2T>C, was confirmed by minigene assay to disrupt exon 3 inclusion, supporting pathogenicity. Most pathogenic alleles are predicted to result in haploinsufficiency.

Whole-exome sequencing (WES) in routine clinical practice further illustrates the utility of detecting NPRL2 variants. In a real-world series of 40 patients with MRI-negative focal epilepsy and positive family history, one patient carried the c.100C>T (p.Arg34Ter) NPRL2 variant, leading to targeted therapy adjustments and refined surgical planning (PMID:28199897). Genetic diagnosis altered antiepileptic drug selection and informed prognosis. Patients with NPRL2-associated focal epilepsy frequently have early onset and may benefit from precision medicine approaches. These data support inclusion of NPRL2 in diagnostic gene panels for focal epilepsy.

Functional studies confirm haploinsufficiency as the pathogenic mechanism for NPRL2 variants. In Drosophila, nprl2 loss-of-function mutants exhibit reduced lifespan, gastrointestinal dysfunction, and elevated TORC1 activity, all of which are rescued by TORC1 inhibition (PMID:31712450). In mammalian cell models, the p.Asp214His variant disrupts NPRL2 interactions with DEPDC5 and NPRL3, impairing GATOR1 complex assembly and causing constitutive mTORC1 activation under amino acid deprivation (PMID:38396745). Conditional animal models of GATOR1 deficiency replicate focal epilepsy and cortical dysplasia phenotypes, further supporting this mechanism (PMID:31639411).

There is no robust conflicting evidence disputing NPRL2’s role in focal epilepsy. Rare missense variants lacking segregation or functional impact underscore the need for careful variant interpretation. No alternative phenotypes have been consistently associated with NPRL2 loss-of-function alleles. Pathogenic variants cluster in domains essential for GATOR1 assembly and mTORC1 regulation, reinforcing specificity. Additional population studies will refine penetrance and expressivity estimates.

In summary, autosomal dominant loss-of-function variants in NPRL2 cause focal epilepsy through mTORC1 pathway deregulation. Strong genetic evidence from multiple probands and familial segregation, together with concordant functional data in cellular and animal models, supports a Strong ClinGen classification. Genetic testing for NPRL2 variants informs clinical decision-making, including tailored antiepileptic therapy and precision medicine strategies. Key take-home: NPRL2 LoF variants define a genetically and mechanistically distinct subtype of focal epilepsy amenable to targeted interventions.

References

• Annals of neurology • 2016 • Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. PMID:26505888
• Epilepsy research • 2017 • Real-world utility of whole exome sequencing with targeted gene analysis for focal epilepsy. PMID:28199897
• Aging • 2019 • The TORC1 inhibitor Nprl2 protects age-related digestive function in Drosophila. PMID:31712450
• Neurobiology of disease • 2020 • Functional screening of GATOR1 complex variants reveals a role for mTORC1 deregulation in FCD and focal epilepsy. PMID:31639411
• International journal of molecular sciences • 2024 • GATOR1 Mutations Impair PI3 Kinase-Dependent Growth Factor Signaling Regulation of mTORC1. PMID:38396745

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