Wang Jing-Yang, Wang Jie, Lu Xin-Guo, Song Wang, Luo Sheng, Zou Dong-Fang, Hua Li-Dong, Peng Qian, Tian Yang, Gao Liang-Di, Liao Wei-Ping, He Na
Department of Neurology, Institute of Neuroscience, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Key Laboratory of Neurogenetics and Channelopathies of the Ministry of Education of China, Guangzhou, China.
Front Mol Neurosci. 2022 May 10;15:861159. doi: 10.3389/fnmol.2022.861159. eCollection 2022.
The encodes polycystin-1, a large transmembrane protein that plays important roles in cell proliferation, apoptosis, and cation transport. Previous studies have identified mutations in autosomal dominant polycystic kidney disease (ADPKD). However, the expression of in the brain is much higher than that in the kidney. This study aimed to explore the association between and epilepsy.
Trios-based whole-exome sequencing was performed in a cohort of 314 patients with febrile seizures or epilepsy with antecedent febrile seizures. The damaging effects of variants was predicted by protein modeling and multiple tools. The genotype-phenotype association of mutations was systematically reviewed and analyzed.
Eight pairs of compound heterozygous missense variants in were identified in eight unrelated patients. All patients suffered from febrile seizures or epilepsy with antecedent febrile seizures with favorable prognosis. All of the 16 heterozygous variants presented no or low allele frequencies in the gnomAD database, and presented statistically higher frequency in the case-cohort than that in controls. These missense variants were predicted to be damaging and/or affect hydrogen bonding or free energy stability of amino acids. Five patients showed generalized tonic-clonic seizures (GTCS), who all had one of the paired missense mutations located in the PKD repeat domain, suggesting that mutations in the PKD domains were possibly associated with GTCS. Further analysis demonstrated that monoallelic mutations with haploinsufficiency of potentially caused kidney disease, compound heterozygotes with superimposed effects of two missense mutations were associated with epilepsy, whereas the homozygotes with complete loss of would be embryonically lethal.
gene was potentially a novel causative gene of epilepsy. The genotype-phenotype relationship of mutations suggested a quantitative correlation between genetic impairment and phenotypic variation, which will facilitate the genetic diagnosis and management in patients with mutations.
[该基因]编码多囊蛋白-1，这是一种大型跨膜蛋白，在细胞增殖、凋亡和阳离子转运中起重要作用。先前的研究已在常染色体显性多囊肾病（ADPKD）中鉴定出[该基因]突变。然而，[该基因]在大脑中的表达远高于在肾脏中的表达。本研究旨在探讨[该基因]与癫痫之间的关联。
对314例热性惊厥患者或有热性惊厥病史的癫痫患者进行基于三联体的全外显子测序。通过蛋白质建模和多种[分析]工具预测变异的有害影响。对[该基因]突变的基因型-表型关联进行系统回顾和分析。
在8例无亲缘关系的患者中鉴定出8对[该基因]的复合杂合错义变异。所有患者均患有热性惊厥或有热性惊厥病史的癫痫，预后良好。所有16个杂合变异在gnomAD数据库中的等位基因频率均无或较低，且在病例队列中的频率在统计学上高于对照组。这些错义变异预计具有有害性和/或影响氨基酸的氢键或自由能稳定性。5例患者表现为全身强直-阵挛性发作（GTCS），他们均有一对错义突变中的一个位于PKD重复结构域，这表明PKD结构域中的突变可能与GTCS有关。进一步分析表明，[该基因]单等位基因突变导致的单倍体不足可能会引发肾脏疾病，两个错义突变具有叠加效应的复合杂合子与癫痫有关，而[该基因]完全缺失的纯合子在胚胎期将是致死的。
[该基因]可能是癫痫的一个新的致病基因。[该基因]突变的基因型-表型关系表明遗传损伤与表型变异之间存在定量相关性，这将有助于对[该基因]突变患者进行基因诊断和管理。
