Objective: This study aims to explore the pathogenic mechanisms of familial cortical myoclonic tremor with epilepsy (FCMTE) using various cellular models, from the perspectives of gene loss of function, RNA toxicity, and repeat peptides toxicity.

Background: FCMTE is an autosomal dominant inherited disease, which is characterized by cortical tremor, commonly accompanied by seizures. The first causative gene SAMD12 and its pathogenic mutation (TTTCA)exp was identified in 2018. Three possible pathogenic mechanisms include: gene loss of function, RNA toxicity and repeat peptides toxicity. However, further research is needed to be explored.

Method: We constructed fibroblast and neuron models derived from FCMTE1 patients, as well as cell line models transfected with FCMTE1 repeat sequence plasmids. Real-time fluorescence quantitative PCR, immunoblotting, RNA fluorescence in situ hybridization and flow cytometry experiments were conducted to preliminarily investigate the potential pathogenic mechanisms of FCMTE1. Exogenous stimulation experiments, transcriptome sequencing and electrophysiological detection were conducted in the constructed FCMTE1 neuron models.

Results: In fibroblast and neuron models, there were no significant differences in SAMD12 mRNA and protein levels between FCMTE1 patients and healthy controls (p>0.05). No labeled protein products were detected in each group of FCMTE1 repeat sequence plasmid-transfected cells, which did not support the existance of repeat peptides toxicity. HEK293T cells and N2A cells transfected with plasmids carrying the FCMTE1 pathogenic (TTTCA)exp formed (UUUCA) RNA foci, accompanied by higher levels of cell apoptosis and LDH release in N2A cells. Compared with neuron models derived from healthy controls, the positive rate of (UUUCA) RNA foci in neuron models derived from FCMTE1 patients significantly increased, and they exhibited higher susceptibility to oxidative stress stimulation. In addition, transcriptome sequencing of neuron models derived from FCMTE1 patients showed multiple entries related to ion channel function, while electrophysiological detection suggested significantly elevated membrane potential levels in neuron models derived from FCMTE1 patients.

Conclusion: the RNA toxicity of (TTTCA)exp is likely the main pathogenic mechanism of FCMTE1

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MDS Abstracts - https://www.mdsabstracts.org/abstract/mechanism-study-of-familial-cortical-myoclonic-tremor-with-epilepsy-type-1-caused-by-pentanucleotide-repeat-expansion-in-the-samd12-gene/