NPRL2 – Familial Focal Epilepsy with Variable Foci

NPRL2 is a subunit of the GATOR1 complex that inhibits mTORC1 signaling. A heterozygous splice-site variant, c.339+2T>C (p.?), was identified by trio whole-exome sequencing in a family with familial focal epilepsy with variable foci and leads to exon 3 skipping as confirmed by minigene assay (PMID:34376795). Affected individuals presented febrile seizures (HP:0002373), infantile spasms (HP:0012469), and focal-onset seizures (HP:0007359) with frontal EEG discharges and showed favorable response to vitamin B6 and topiramate. No additional unrelated families have been reported, limiting genetic evidence to a single pedigree. Functional studies of epilepsy-linked NPRL2 missense variants (p.Thr110Ser, p.Asp214His, p.Leu105Pro) demonstrate loss-of-function and increased mTORC1 activity (PMID:38396745). In contrast, rare NPRL2 missense variants in a focal epilepsy cohort did not cosegregate with disease (PMID:36604176), indicating variable penetrance. Mechanistically, NPRL2 haploinsufficiency disrupts GATOR1 assembly and impairs mTORC1 repression, supporting a pathogenic role. Key take-home: NPRL2 haploinsufficiency causes autosomal dominant familial focal epilepsy via mTORC1 dysregulation, warranting inclusion in diagnostic gene panels.

References

• Journal of human genetics • 2022 • A splicing variation in NPRL2 causing familial focal epilepsy with variable foci: additional cases and literature review. PMID:34376795
• International journal of molecular sciences • 2024 • GATOR1 Mutations Impair PI3 Kinase-Dependent Growth Factor Signaling Regulation of mTORC1. PMID:38396745
• Journal of medical genetics • 2023 • Clinical and genetic features of GATOR1 complex-associated epilepsy. PMID:36604176

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