A novel autism-associated KCNB1 mutation dramatically slows Kv2.1 potassium channel activation, deactivation and inactivation

IF 4.2 3区 医学 Q2 NEUROSCIENCES Frontiers in Cellular Neuroscience Pub Date : 2024-07-29 DOI:10.3389/fncel.2024.1438101
Rían W. Manville, Samantha D. Block, Claire L. Illeck, Jessica Kottmeier, Richard Sidlow, Geoffrey W. Abbott
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Abstract

KCNB1, on human chromosome 20q13.3, encodes the alpha subunit of the Kv2.1 voltage gated potassium channel. Kv2.1 is ubiquitously expressed throughout the brain and is critical in controlling neuronal excitability, including in the hippocampus and pyramidal neurons. Human KCNB1 mutations are known to cause global development delay or plateauing, epilepsy, and behavioral disorders. Here, we report a sibling pair with developmental delay, absence seizures, autism spectrum disorder, hypotonia, and dysmorphic features. Whole exome sequencing revealed a heterozygous variant of uncertain significance (c. 342 C&gt;A), p. (S114R) in KCNB1, encoding a serine to arginine substitution (S114R) in the N-terminal cytoplasmic region of Kv2.1. The siblings’ father demonstrated autistic features and was determined to be an obligate KCNB1 c. 342 C&gt;A carrier based on familial genetic testing results. Functional investigation of Kv2.1-S114R using cellular electrophysiology revealed slowing of channel activation, deactivation, and inactivation, resulting in increased net current after longer membrane depolarizations. To our knowledge, this is the first study of its kind that compares the presentation of siblings each with a KCNB1 disorder. Our study demonstrates that Kv2.1-S114R has profound cellular and phenotypic consequences. Understanding the mechanisms underlying KCNB1-linked disorders aids clinicians in diagnosis and treatment and provides potential therapeutic avenues to pursue.
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一种新型自闭症相关 KCNB1 基因突变可显著减缓 Kv2.1 钾通道的激活、失活和失活速度
KCNB1 位于人类染色体 20q13.3 上,编码 Kv2.1 电压门控钾通道的 alpha 亚基。Kv2.1 在整个大脑中普遍表达,是控制神经元兴奋性的关键,包括在海马和锥体神经元中。已知人类 KCNB1 基因突变会导致整体发育延迟或停滞、癫痫和行为紊乱。在此,我们报告了一对患有发育迟缓、失神发作、自闭症谱系障碍、肌张力低下和畸形特征的兄弟姐妹。全外显子组测序发现了 KCNB1 中的一个意义不确定的杂合变异(c. 342 C&gt;A),p. (S114R),编码 Kv2.1 N 端胞质区域中丝氨酸到精氨酸的置换 (S114R)。这对兄妹的父亲表现出自闭症特征,并根据家族遗传检测结果被确定为 KCNB1 c. 342 C&gt;A 的强制性携带者。利用细胞电生理学对 Kv2.1-S114R 进行的功能研究发现,通道激活、失活和失活的速度减慢,导致较长时间膜去极化后的净电流增加。据我们所知,这是第一项对患有 KCNB1 紊乱的同胞兄弟姐妹的表现进行比较的同类研究。我们的研究表明,Kv2.1-S114R 会对细胞和表型产生深远的影响。了解 KCNB1 相关疾病的发病机制有助于临床医生进行诊断和治疗,并提供了潜在的治疗途径。
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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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