NPRL3 – Focal Epilepsy

NPRL3 encodes a component of the GATOR1 complex, a key negative regulator of mTORC1 signaling in neurons. Loss-of-function (LoF) mutations in GATOR1 subunits have been implicated in focal epilepsy syndromes, often presenting with pharmacoresistant seizures or focal cortical dysplasia. Early linkage and sequencing studies identified NPRL3 as a novel epilepsy gene, prompting targeted genetic screens in familial and sporadic cases.

Two unrelated Chinese families with focal epilepsy were found to carry heterozygous truncating and splice-site NPRL3 variants. In family E1, a c.954C>A (p.Tyr318Ter) variant segregated with seizures in two siblings, although both mothers were asymptomatic ([PMID:36685832]). In family E2, a canonical splice acceptor mutation c.1545-1G>C led to exon loss and recurrent focal seizures in the proband ([PMID:36685832]). A second study in two brothers with FCD IIA identified a germline NPRL3 frameshift c.48delG (p.Ser17AlafsTer70) alongside a somatic WNT2 hit, supporting an intersecting dual-pathway model ([PMID:35097204]).

First cousin sibling pairs with focal epilepsy and FCD IIa carried heterozygous NPRL3 frameshift variants, with mTORC1 activation demonstrated by phospho-S6 immunostaining in resected brain tissue ([PMID:26285051]). Screening of 52 unrelated FCD patients revealed two additional NPRL3 mutation carriers ([PMID:26285051]). In a European cohort of 93 focal epilepsy probands, targeted sequencing detected one pathogenic NPRL3 mutation among GATOR1 genes ([PMID:27173016]).

A large multi-center study of 404 unrelated focal epilepsy patients identified five distinct NPRL3 variants among probands, with linkage analysis in multiplex families confirming autosomal dominant segregation and reduced penetrance ([PMID:26505888]). A Serbian referral cohort (n=96) found a single NPRL3 missense variant of uncertain significance, highlighting the predominance of LoF alleles in clinical cases ([PMID:36848747]).

A six-generation Chinese pedigree with familial focal epilepsy with variable foci (FFEVF) harbored a novel nonsense variant c.316C>T (p.Gln106Ter) segregating across four generations, with decreased NPRL3 mRNA and protein levels and increased downstream phospho-p70 S6 kinase signaling in carriers ([PMID:34868250]). Another FFEVF family with c.1137dupT (p.Pro380SerfsTer?) showed variable age at onset (4 months–31 years) and EEG abnormalities despite normal MRI, underlining phenotypic heterogeneity ([PMID:37099548]).

To date, over 30 distinct NPRL3 LoF variants—nonsense, frameshift, and canonical splice-site mutations—have been reported in focal epilepsy, with no clear founder alleles. A few missense variants (e.g., p.Arg256Pro) impair NPRL3–NPRL2 binding and destabilize the GATOR1 complex, but most pathogenic alleles truncate the protein or disrupt splicing ([PMID:39729176]).

Functional studies confirm that NPRL3 haploinsufficiency leads to mTORC1 hyperactivation. In vitro assays of patient-derived cells and GATOR1 functional screens demonstrate impaired mTOR repression by mutant NPRL3 ([PMID:31639411]). Drosophila nprl3 knockdown models exhibit seizure-like behavior and synaptic defects, and patient-derived cortical organoids recapitulate enlarged organoid size and increased p-S6 levels, providing in vivo and in vitro concordance with human phenotypes ([PMID:37071290], [PMID:39729176]).

Despite high penetrance in many families, incomplete penetrance is observed: obligate carriers without seizures have been documented, necessitating careful genetic counseling. NPRL3 genetic testing should be prioritized in patients with focal epilepsy or focal cortical dysplasia, as confirmation of a pathogenic NPRL3 variant informs diagnosis, recurrence risk, and potential mTOR-targeted therapeutic strategies.

References

• Frontiers in Genetics | 2022 | Identification of two rare NPRL3 variants in two Chinese families with familial focal epilepsy with variable foci 3: NGS analysis with literature review. PMID:36685832
• Neurology: Genetics | 2022 | Evidence for a Dual-Pathway, 2-Hit Genetic Model for Focal Cortical Dysplasia and Epilepsy. PMID:35097204
• Annals of Neurology | 2016 | Familial cortical dysplasia caused by mutation in the mammalian target of rapamycin regulator NPRL3. PMID:26285051
• Annals of Neurology | 2016 | Mutations in the mammalian target of rapamycin pathway regulators NPRL2 and NPRL3 cause focal epilepsy. PMID:26505888
• PLoS One | 2023 | The clinical features of familial focal epilepsy with variable foci and NPRL3 gene variant. PMID:37099548
• Neurobiology of Disease | 2020 | Functional screening of GATOR1 complex variants reveals a role for mTORC1 deregulation in FCD and focal epilepsy. PMID:31639411
• Science China Life Sciences | 2023 | Functional characterization of novel NPRL3 mutations identified in three families with focal epilepsy. PMID:37071290
• Journal of Molecular Neuroscience | 2024 | Identifying the Pathogenicity of a Novel NPRL3 Missense Mutation Using Personalized Cortical Organoid Model of Focal Cortical Dysplasia. PMID:39729176

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