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.

Keywords: KCNA1; Kv1.1; SUDEP; epilepsy; episodic ataxia; genetic modifiers; musculoskeletal; myokymia; nystagmus; respiration.

Figure 1

Map of KCNA1 mutations associated with human disease. Human mutations in KCNA1 were mapped across the protein and color-coded to indicate their clinically documented disease association. Circles with multiple colors represent mutations with multiple phenotypes. Multiple circles at a given amino acid position represent different amino acid substitutions at that location (e.g., A242P/S/T) and their associated disease manifestation. The blue star indicates the RNA editing position. The identity of the various transmembrane domains is indicated as S1–S6. Abbreviations: EA1, episodic ataxia type 1; PKD, paroxysmal kinesigenic dyskinesia.