Manville Rían W, Block Samantha D, Illeck Claire L, Kottmeier Jessica, Sidlow Richard, Abbott Geoffrey W
Bioelectricity Laboratory, Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA, United States.
Faculty of Health Sciences, Ben-Gurion University of the Negev, Be'er Sheva, Israel.
Front Cell Neurosci. 2024 Jul 29;18:1438101. doi: 10.3389/fncel.2024.1438101. eCollection 2024.
, 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 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>A), p. (S114R) in , 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 c. 342 C>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 disorder. Our study demonstrates that Kv2.1-S114R has profound cellular and phenotypic consequences. Understanding the mechanisms underlying -linked disorders aids clinicians in diagnosis and treatment and provides potential therapeutic avenues to pursue.
位于人类染色体20q13.3上，编码Kv2.1电压门控钾通道的α亚基。Kv2.1在整个大脑中广泛表达，对控制神经元兴奋性至关重要，包括在海马体和锥体神经元中。已知人类突变会导致全球发育迟缓或发育停滞、癫痫和行为障碍。在此，我们报告一对患有发育迟缓、失神发作、自闭症谱系障碍、肌张力减退和畸形特征的同胞。全外显子组测序揭示了一个意义未明的杂合变异（c.342 C>A），位于 中，编码Kv2.1 N端胞质区域中丝氨酸到精氨酸的替换（S114R）。根据家族基因检测结果，这对同胞的父亲表现出自闭症特征，被确定为c.342 C>A的必然携带者。使用细胞电生理学对Kv2.1 - S114R进行功能研究发现，通道激活、失活和去激活减慢，导致更长时间膜去极化后净电流增加。据我们所知，这是同类研究中首次比较患有 疾病的同胞的表现。我们的研究表明，Kv2.1 - S114R具有深远的细胞和表型后果。了解与 相关疾病的潜在机制有助于临床医生进行诊断和治疗，并提供潜在的治疗途径以供探索。
