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.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:89542 |
| Date | 06 February 2024 |
| Creators | Döring, Jan H., Schröter, Julian, Jüngling, Jerome, Biskup, Saskia, Klotz, Kerstin A., Bast, Thomas, Dietel, Tobias, Korenke, G. Christoph, Christoph, Sophie, Brennenstuhl, Heiko, Rubboli, Guido, Moller, Rikke S., Lesca, Gaetan, Chaix, Yves, Kölker, Stefan, Hoffmann, Georg F., Lemke, Johannes R., Syrbe, Steffen |
| Publisher | MDPI |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 2824 |
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