Abstract
Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants.
Highlights
Potassium channels are involved in many vital processes such as neuronal excitability, neurotransmitter release, and cellular osmoregulation [1,2]
We identified 115 individuals with pathogenic and likely pathogenic (P/LP) KCNA2 variants from 28 publications (78 cases) and ClinVar database entries (37 cases)
Thirty different alterations of KCNA2 are on record to date, with 26 single-nucleotide variants (SNV), one in-frame deletion, and three different deletions (Tables 1 and 2)
Summary
Potassium channels are involved in many vital processes such as neuronal excitability, neurotransmitter release, and cellular osmoregulation [1,2]. KCNA2, encoding for the voltage-gated potassium channel subfamily A member 2 (Kv1.2, OMIM * 176262) is a member of the shaker-like delayed rectifier potassium channel family [3]. It is predominantly expressed in axons and presynaptic terminals of the central nervous system [4,5]. Homo- or heterotetramers formed by α-subunits containing variable proportions of Kvsubfamily members contribute to functional channel characteristics [6]. Kv1.2 consists of six transmembrane segments (S1–S6) forming the voltage-sensing domain (S4) and the ion-conducting pore (S5-S6) with its selectivity filter localized in the pore loop [7,8]. Several antibody-mediated neurological diseases in children and adults have been linked to proteins associated with Kv1 channel components, such as leucine-rich glioma-inactivated 1, contactin-associated protein 2, and Kv1 channel subunits [11,12]
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