Abstract
Mutations in the KCNA1 gene, which encodes voltage-gated Kv1.1 potassium channel α-subunits, cause a variety of human diseases, complicating simple genotype–phenotype correlations in patients. KCNA1 mutations are primarily associated with a rare neurological movement disorder known as episodic ataxia type 1 (EA1). However, some patients have EA1 in combination with epilepsy, whereas others have epilepsy alone. KCNA1 mutations can also cause hypomagnesemia and paroxysmal dyskinesia in rare cases. Why KCNA1 variants are associated with such phenotypic heterogeneity in patients is not yet understood. In this review, literature databases (PubMed) and public genetic archives (dbSNP and ClinVar) were mined for known pathogenic or likely pathogenic mutations in KCNA1 to examine whether patterns exist between mutation type and disease manifestation. Analyses of the 47 deleterious KCNA1 mutations that were identified revealed that epilepsy or seizure-related variants tend to cluster in the S1/S2 transmembrane domains and in the pore region of Kv1.1, whereas EA1-associated variants occur along the whole length of the protein. In addition, insights from animal models of KCNA1 channelopathy were considered, as well as the possible influence of genetic modifiers on disease expressivity and severity. Elucidation of the complex relationship between KCNA1 variants and disease will enable better diagnostic risk assessment and more personalized therapeutic strategies for KCNA1 channelopathy.
Highlights
Mutations in the voltage-gated potassium channel gene KCNA1 underlie a myriad of human diseases, thereby preventing simple genotype–phenotype correlations in patients
To begin to decipher the complex genotype–phenotype relationships associated with KCNA1 channelopathy and episodic ataxia type 1 (EA1), this review examines all known human KCNA1 single nucleotide polymorphisms (SNPs) that have been identified as pathogenic or likely pathogenic to date
Post mortem analysis showed that the patient harbored non-synonymous SNPs and copy number variant (CNV) in several different ion channel genes, including a de novo non-synonymous SNP (A1783V) in the voltage-gated sodium channel SCN1A which was previously found in another severe myoclonic epilepsy of infancy (SMEI) patient [88].The CNV in KCNA1 resulted in five extra copies of the region that extends from the PVP motif to the end of the S6 transmembrane helix, which may render the protein greatly impaired or non-functional [88]
Summary
Mutations in the voltage-gated potassium channel gene KCNA1 underlie a myriad of human diseases, thereby preventing simple genotype–phenotype correlations in patients. The primary disease associated with KCNA1 mutations is episodic ataxia type 1 (EA1), a rare neurological movement disorder. In some rare instances, KCNA1 mutations cause hypomagnesemia, paroxysmal dyskinesia, and myokymia. To begin to decipher the complex genotype–phenotype relationships associated with KCNA1 channelopathy and EA1, this review examines all known human KCNA1 single nucleotide polymorphisms (SNPs) that have been identified as pathogenic or likely pathogenic to date. The disease phenotype associated with each variant is examined to determine whether patterns exist between types of mutations and manifestation of disease. The role of genetic modifiers in KCNA1 channelopathy is discussed as another potential factor affecting genotype–phenotype relationships in patients
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