进行性肌阵挛性癫痫的复合杂合KCTD7变异。

IF 1.8 4区 医学 Q3 GENETICS & HEREDITY
Journal of neurogenetics Pub Date : 2021-03-01 Epub Date: 2021-05-10 DOI:10.1080/01677063.2021.1892095
Elizabeth A Burke, Morgan Sturgeon, Diane B Zastrow, Liliana Fernandez, Cameron Prybol, Shruti Marwaha, Edward P Frothingham, Patricia A Ward, Christine M Eng, Laure Fresard, Stephen B Montgomery, Gregory M Enns, Paul G Fisher, Lynne A Wolfe, Brian Harding, Blake Carrington, Kevin Bishop, Raman Sood, Yan Huang, Abdel Elkahloun, Camilo Toro, Alexander G Bassuk, Matthew T Wheeler, Thomas C Markello, William A Gahl, May Christine V Malicdan
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引用次数: 1

摘要

KCTD7是含钾通道四聚结构域蛋白家族的成员,与进行性肌阵挛性癫痫(PME)有关,其特征是肌阵挛、癫痫和神经功能恶化。在这里,我们报告了来自两个不相关家族的四个受影响个体,我们通过外显子组测序鉴定了KCTD7复合杂合单核苷酸变异。RNAseq用于检测由第二家族的同义变体产生的无注释剪接连接。过表达患者变异等位基因的神经母细胞瘤细胞的全细胞膜片钳分析显示钾调控异常。虽然所有4名患者都经历了PME的许多常见临床特征,但他们也表现出以前未报道的可变表型,包括自主神经异常,脑部病理发现包括丘脑显着减少,以及肌阵挛性癫痫的缺乏。为了进一步了解这种疾病的发病机制,我们使用锌指核酸酶来产生kctd7基因敲除的斑马鱼。Kctd7纯合突变体表现出基因表达的全局失调和c-fos转录的增加,这在之前的动物模型中与癫痫活动相关。总之,这些发现扩大了已知的kctd7相关PME的表型谱,为未来的研究报告了一个新的动物模型,并为该疾病提供了有价值的见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Compound heterozygous KCTD7 variants in progressive myoclonus epilepsy.

KCTD7 is a member of the potassium channel tetramerization domain-containing protein family and has been associated with progressive myoclonic epilepsy (PME), characterized by myoclonus, epilepsy, and neurological deterioration. Here we report four affected individuals from two unrelated families in which we identified KCTD7 compound heterozygous single nucleotide variants through exome sequencing. RNAseq was used to detect a non-annotated splicing junction created by a synonymous variant in the second family. Whole-cell patch-clamp analysis of neuroblastoma cells overexpressing the patients' variant alleles demonstrated aberrant potassium regulation. While all four patients experienced many of the common clinical features of PME, they also showed variable phenotypes not previously reported, including dysautonomia, brain pathology findings including a significantly reduced thalamus, and the lack of myoclonic seizures. To gain further insight into the pathogenesis of the disorder, zinc finger nucleases were used to generate kctd7 knockout zebrafish. Kctd7 homozygous mutants showed global dysregulation of gene expression and increased transcription of c-fos, which has previously been correlated with seizure activity in animal models. Together these findings expand the known phenotypic spectrum of KCTD7-associated PME, report a new animal model for future studies, and contribute valuable insights into the disease.

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来源期刊
Journal of neurogenetics
Journal of neurogenetics 医学-神经科学
CiteScore
4.40
自引率
0.00%
发文量
13
审稿时长
>12 weeks
期刊介绍: The Journal is appropriate for papers on behavioral, biochemical, or cellular aspects of neural function, plasticity, aging or disease. In addition to analyses in the traditional genetic-model organisms, C. elegans, Drosophila, mouse and the zebrafish, the Journal encourages submission of neurogenetic investigations performed in organisms not easily amenable to experimental genetics. Such investigations might, for instance, describe behavioral differences deriving from genetic variation within a species, or report human disease studies that provide exceptional insights into biological mechanisms
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