| چکیده انگلیسی مقاله |
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 co-segregated 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. |
| نویسندگان مقاله |
| Faezeh Jamali
Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran|Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| Mohammad Shariati
Department of Neurology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran|Academic Center for Education, Culture, and Research (ACECR)-Khorasan Razavi, Mashhad, Iran
| Mohammadtagi Farzadfard
Department of Neurology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| Juliane Winkelmann
Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany|Institut Für Humangenetik, Technische Universität München, School of Medicine and Health, Munich, Germany|Munich Cluster for Systems Neurology, SyNergy, Munich, Germany
| Mohsen Foroughipour
Department of Neurology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| Mir Salar Kahaei
Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| Ariane Sadr-Nabavi
Department of Medical Genetics and Molecular Medicine, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran|Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran|Department of Neurology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| Michael Zech
Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany|Institut Für Humangenetik, Technische Universität München, School of Medicine and Health, Munich, Germany|Institute for Advanced Study, Technical University of Munich, Garching, Germany
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