A novel loss-of-function KCNB1 gene variant in a twin with global developmental delay and seizures.

IF 4.2 3区 医学 Q2 NEUROSCIENCES
Frontiers in Cellular Neuroscience Pub Date : 2024-10-14 eCollection Date: 2024-01-01 DOI:10.3389/fncel.2024.1477989
Rían W Manville, Claire L Illeck, Cesar Santos, Richard Sidlow, Geoffrey W Abbott
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Abstract

Human voltage-gated potassium (Kv) channels are expressed by a 40-member gene family that is essential for normal electrical activity and is closely linked to various excitability disorders. Function-altering sequence variants in the KCNB1 gene, which encodes the neuronally expressed Kv2.1 channel, are associated with neurodevelopmental disorders including developmental delay with or without epileptic activity. In this study, we describe a 40-month-old fraternal twin who presented with severe neurodevelopmental delay. Electroencephalogram recordings at 19 months of age revealed poor sleep architecture and the presence of multifocal epileptiform discharges. The individual's fraternal twin was neurotypical, and there was no family history of neurodevelopmental delay or seizures. Whole genome sequencing at 33 months of age for the proband revealed a de novo variant in KCNB1 [c.1154C > T/p.Pro385Leu], encoding a proline-to-leucine substitution at residue 385, in the extracellular region immediately preceding Kv2.1 transmembrane segment 6 (S6). Cellular electrophysiological analysis of the effects of the gene variant in heterologously expressed Kv2.1 demonstrated that homozygous Kv2.1-P385L channels were completely non-functional. Channels generated by a 50/50 expression of wild-type Kv2.1 and Kv2.1-P385L, designed to mimic the proband's heterozygous status, revealed a partially dominant-negative effect, resulting in an 81% reduction in current magnitude. The dramatic loss of function in Kv2.1 is the most likely cause of the severe developmental delay and seizure activity in the proband, further enriching our phenotypic understanding of KCNB1 developmental encephalopathies.

在一对患有全面发育迟缓和癫痫发作的双胞胎中发现了一种新型功能缺失的 KCNB1 基因变异。
人类电压门控钾(Kv)通道由一个由 40 个成员组成的基因家族表达,该家族对正常的电活动至关重要,并与各种兴奋性疾病密切相关。编码神经表达的 Kv2.1 通道的 KCNB1 基因的功能改变序列变异与神经发育障碍有关,包括伴有或不伴有癫痫活动的发育迟缓。在本研究中,我们描述了一对 40 个月大的异卵双胞胎,他们患有严重的神经发育迟缓。19 个月大时的脑电图记录显示其睡眠结构不良,并出现多灶性癫痫样放电。该患者的异卵双胞胎神经发育正常,家族中没有神经发育迟缓或癫痫发作病史。该患者在33个月大时进行的全基因组测序发现,KCNB1存在一个新变异[c.1154C > T/p.Pro385Leu],编码在紧接Kv2.1跨膜区6(S6)之前的胞外区域385位脯氨酸到亮氨酸的置换。对该基因变异在异源表达的 Kv2.1 中的影响进行的细胞电生理分析表明,同基因 Kv2.1-P385L 通道完全没有功能。野生型 Kv2.1 和 Kv2.1-P385L 各表达 50/50 所产生的通道(旨在模拟原告的杂合状态)显示出部分显性负效应,导致电流幅度降低 81%。Kv2.1功能的急剧丧失很可能是导致该受试者严重发育迟缓和癫痫活动的原因,这进一步丰富了我们对KCNB1发育性脑病的表型认识。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
7.90
自引率
3.80%
发文量
627
审稿时长
6-12 weeks
期刊介绍: Frontiers in Cellular Neuroscience is a leading journal in its field, publishing rigorously peer-reviewed research that advances our understanding of the cellular mechanisms underlying cell function in the nervous system across all species. Specialty Chief Editors Egidio D‘Angelo at the University of Pavia and Christian Hansel at the University of Chicago are supported by an outstanding Editorial Board of international researchers. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to researchers, academics, clinicians and the public worldwide.
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