Abstract
BACKGROUND: The Midasin AAA (ATPase associated with various activities) ATPase 1 (MDN1) gene, a member of the AAA protein family, plays a crucial role in ribosome maturation. MDN1 is expressed in the human brain throughout life, especially during early development and adulthood. However, MDN1 variants have not been previously reported in patients with epilepsy. This study aims to explore the association between MDN1 variants and epilepsy. METHODS: Trios-based whole-exome sequencing was performed in a cohort of patients with epilepsy susceptibility from the China Epilepsy Gene 1.0 Project. The excess, damaging effects, and molecular subregional implications of variants, as well as the spatio-temporal expression of MDN1, were analyzed to validate the gene-disease association. RESULTS: Compound heterozygous variants in MDN1 were identified in five unrelated patients with febrile seizures or secondary epilepsy. Three patients presented with febrile seizures/epilepsy with febrile seizures plus, while two patients developed epilepsy secondary to brain damage (five or seven years after). These variants were either absent or present at low frequencies in the control group, and exhibited statistically significant higher frequencies in the case group compared to controls. All the missense variants were predicted to be damaging by at least one in silico tool. In each pair of compound heterozygous variants, one allele was located in the AAA2-AAA3 domains, while the other allele was located in the linker domain or its vicinity. In contrast, most of the variants from the asymptomatic control group were located outside the AAA domains, suggesting a molecular subregional implication of the MDN1 variants. CONCLUSIONS: MDN1 is potentially a susceptibility gene for epilepsy.