TY  - JOUR
AB  - Objective(s): Genetic generalized epilepsy (GGE) is a common subtype of epilepsy characterized by generalized seizure types, with an unclear etiology and recognized genetic contribution to its susceptibility. Although genetic factors play a significant role, the precise mechanisms and causative variants underlying GGE remain poorly understood. This study aimed to identify the genetic basis of GGE. Materials and Methods: Whole exome sequencing (WES) was performed in eight consanguineous GGE families. Sanger sequencing was conducted to validate the WES findings and confirm variant segregation within the families. RNA-seq data (GSE185632) and in silico analyses were used to assess gene expression and variant pathogenicity. Results: A rare nonsense variant in exon 13 of Calpain 7 (CAPN7, NM_014296.3: c.1454G>A; p.Trp485Ter) was identified and determined to be pathogenic according to the American College of Medical Genetics and Genomics (ACMG) criteria (PVS1, PM2, PP4, and PP1). The variant cosegregated with the disease in the family. RNA-seq analysis of epilepsy transcriptomes revealed significant down-regulation of this gene (log2FC= -0.84, padj = 0.016). Complementary computational analyses demonstrated strong evolutionary constraint and pathogenic signatures, further supporting its disease association. CAPN7 negatively perturbate endometrial stromal cell decidualization in epithelial-mesenchymal transition via AKT pathway. The proteolytic activity of CAPN7 is associated with degradation of EGFR. Conclusion: This study provides novel insight on the association of CAPN7 in GGE, highlighting its potential contribution to epilepsy pathogenesis. Further research is required to gather additional evidence and elucidate the molecular mechanisms underlying the clinical manifestations associated with CAPN7 variants.
AU  - Jamali, F.*
AU  - Shariati, M.*
AU  - Farzadfard, M.*
AU  - Winkelmann, J.
AU  - Foroughipour, M.*
AU  - Kahaei, M.S.*
AU  - Sadr-Nabavi, A.*
AU  - Zech, M.
C1  - 75417
C2  - 57965
CY  - Vice-chancellor For Res Ctr Off Ijbms, Daneshgah St, Po Box 9138813944 - 445, Mashhad, 00000, Iran
SP  - 1328-1334
TI  - Calpain 7 as a novel candidate gene in genetic generalized epilepsy.
JO  - Iran. J. Basic Med. Sci.
VL  - 28
IS  - 10
PB  - Mashhad Univ Med Sciences
PY  - 2025
SN  - 2008-3866
ER  -