Wen Qianru, Zhang Dongming, Ding Yan, Luo Sheng, Huang Qiang, Zhu Junhui, Li Yongxin, Liu Wenhui, Wang Pengyu, Li Xian, Lin Zisheng, Wang Yaying, Liang Xiaoyu, Liao Weiping, Wang Jie, Meng Heng
Department of Neurology, The Sixth Affiliated Hospital of Jinan University, Dongguan, 523573, China.
Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, China.
Acta Epileptol. 2025 Mar 3;7(1):17. doi: 10.1186/s42494-025-00209-3.
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.
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.
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.
MDN1 is potentially a susceptibility gene for epilepsy.
迈达斯因AAA（与多种活动相关的ATP酶）ATP酶1（MDN1）基因是AAA蛋白家族的成员，在核糖体成熟过程中起关键作用。MDN1在人的一生中均有表达，尤其是在早期发育和成年期。然而，此前尚未有癫痫患者中MDN1变异的报道。本研究旨在探讨MDN1变异与癫痫之间的关联。
对来自中国癫痫基因1.0项目的癫痫易感性患者队列进行基于三联体的全外显子测序。分析变异的过量、有害效应和分子亚区域影响，以及MDN1的时空表达，以验证基因与疾病的关联。
在5例不相关的热性惊厥或继发性癫痫患者中鉴定出MDN1的复合杂合变异。3例患者表现为热性惊厥/热性惊厥附加症癫痫，而2例患者继发于脑损伤（5或7年后）的癫痫。这些变异在对照组中不存在或低频出现，与对照组相比，在病例组中出现频率具有统计学意义的更高。所有错义变异至少被一种计算机工具预测为有害。在每对复合杂合变异中，一个等位基因位于AAA2 - AAA3结构域，而另一个等位基因位于连接结构域或其附近。相比之下，无症状对照组的大多数变异位于AAA结构域之外，提示MDN1变异的分子亚区域影响。
MDN1可能是癫痫的一个易感基因。
