Novel Genetic Variants Expand the Functional, Molecular, and Pathological Diversity of KCNA1 Channelopathy

Abstract

The KCNA1 gene encodes Kv1.1 voltage-gated potassium channel α subunits, which are crucial for maintaining healthy neuronal firing and preventing hyperexcitability. Mutations in the KCNA1 gene can cause several neurological diseases and symptoms, such as episodic ataxia type 1 (EA1) and epilepsy, which may occur alone or in combination, making it challenging to establish simple genotype–phenotype correlations. Previous analyses of human KCNA1 variants have shown that epilepsy-linked mutations tend to cluster in regions critical for the channel’s pore, whereas EA1-associated mutations are evenly distributed across the length of the protein. In this review, we examine 17 recently discovered pathogenic or likely pathogenic KCNA1 variants to gain new insights into the molecular genetic basis of KCNA1 channelopathy. We provide the first systematic breakdown of disease rates for KCNA1 variants in different protein domains, uncovering potential location biases that influence genotype–phenotype correlations. Our examination of the new mutations strengthens the proposed link between the pore region and epilepsy and reveals new connections between epilepsy-related variants, genetic modifiers, and respiratory dysfunction. Additionally, the new variants include the first two gain-of-function mutations ever discovered for KCNA1, the first frameshift mutation, and the first mutations located in the cytoplasmic N-terminal domain, broadening the functional and molecular scope of KCNA1 channelopathy. Moreover, the recently identified variants highlight emerging links between KCNA1 and musculoskeletal abnormalities and nystagmus, conditions not typically associated with KCNA1. These findings improve our understanding of KCNA1 channelopathy and promise to enhance personalized diagnosis and treatment for individuals with KCNA1-linked disorders.

Unusual Voltage-Gated Sodium and Potassium Channelopathies Related to Epilepsy

“… 34 Missense LoF variants of KCNA1 are associated with various types of epilepsy including DEE, episodic ataxia, myokymia, musculoskeletal abnormalities, and nystagmus. 35 36 Epilepsy phenotypes were associated with the pore-forming transmembrane domain of the protein, which was also the case in our patient. Although the c.1112C>T variant was previously reported by our institution, here we have additionally specified its clinical characteristics.…”

Genome-Wide Association Studies for Body Conformation Traits in Korean Holstein Population

“…The KCNA1 gene encodes the voltage-gated potassium channel Kv1.1 protein, which plays a major role in refractory focal epilepsy disease in humans and is essential for proper brain development [ 41 ]. Furthermore, the recently identified variants underscore emerging connections between KCNA1 and musculoskeletal abnormalities [ 42 ].…”

Newly Identified KCNA3 Gene Variants Put the “Excite”-ment Back in Kv1.3 Channelopathy

“… 5 About 100 genes are implicated in DEE, with approximately one-third encoding ion channels or transporters, including KCNA1 and KCNA2 , which are closely related to KCNA3 . 6 , 7 …”

“…Kv1 channels share a similar structure with 6 transmembrane segments (S1-S6) that contain critical voltage-sensing (S1-S4) and pore domains (S5-S6). 7 The transmembrane regions are flanked by N- and C-terminal intracellular domains that have less understood functions. Among the 13 de novo Kv1.3 variants identified, 9 mapped to the S6 transmembrane segment or S5-S6 linker of the pore domain, which allows K + flux across the membrane.…”

“…Missense mutations affecting the corresponding amino acid in Kv1.1 and Kv1.2 also cause DEE, reinforcing the association between the PVP motif in Kv1 channels and severe epilepsy. 7 …”