Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province, Department of Neurology of the Second Affiliated Hospital, Institute of Neuroscience, Guangzhou Medical University, Ministry of Education of China, Guangzhou, China.
Department of Pediatric Neurology, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
Sci Rep. 2024 Oct 26;14(1):25575. doi: 10.1038/s41598-024-77039-9.
The LONP1 gene encodes Lon protease, which is responsible for degrading damaged or misfolded proteins and binding mitochondrial DNA. Previously, LONP1 variants have been identified in patients with cerebral, ocular, dental, auricular, and skeletal anomalies (CODAS syndrome) and mitochondrial diseases. Seizures were occasionally observed. However, the association between LONP1 and epilepsy remains elusive. In this study, we performed trio-based whole-exome sequencing in a cohort of 450 patients with unexplained epilepsy and identified four pairs of compound heterozygous LONP1 variants in four unrelated cases. All patients exhibited good responses to anti-seizure medications and demonstrated no developmental delay or intellectual disabilities. The variant allele frequencies observed in this study were absent or low in the general population and were significantly lower than those of benign variants. At least one variant in each biallelic pair affected hydrogen bonding and/or altered protein stability. The CODAS syndrome-associated variants were concentrated in the AAA+ module, especially the α domain. Four of the five mitochondrial disease-associated variants were located in the AAA + domain and the NTD and NTD subdomains. In contrast, each of the biallelic variants from the patients with pure epilepsy had one variant located in the linker domain, and the other variant located in the mitochondrial targeting sequence or P domain. This study suggested that LONP1 gene is potentially a novel candidate gene for pure epilepsy. The phenotypic variation is associated with the sub-regional effects of variants.
LONP1 基因编码 Lon 蛋白酶，该酶负责降解受损或错误折叠的蛋白质并结合线粒体 DNA。先前，在患有脑、眼、牙、耳和骨骼异常（CODAS 综合征）和线粒体疾病的患者中已鉴定出 LONP1 变体。偶尔会观察到癫痫发作。然而，LONP1 与癫痫之间的关联仍然难以捉摸。在这项研究中，我们对 450 名原因不明的癫痫患者进行了基于三亲的全外显子组测序，在四个无关病例中鉴定出了四个 LONP1 变体的复合杂合子对。所有患者对抗癫痫药物均有良好反应，且无发育迟缓或智力障碍。本研究中观察到的变异等位基因频率在普通人群中缺失或较低，明显低于良性变异。每个双等位基因对中的至少一个变体影响氢键形成和/或改变蛋白质稳定性。与 CODAS 综合征相关的变体集中在 AAA+ 模块，特别是α结构域。与线粒体疾病相关的五个变体中有四个位于 AAA+ 结构域和 NTD 及 NTD 亚结构域。相比之下，来自单纯性癫痫患者的每个双等位基因变体都有一个变体位于连接域，另一个变体位于线粒体靶向序列或 P 结构域。本研究表明，LONP1 基因可能是单纯性癫痫的一个新的候选基因。表型的变异与变体的亚区域效应有关。
