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Döring, Jan H. [Author]; Schröter, Julian [Author]; Jüngling, Jerome [Author]; Biskup, Saskia [Author]; Klotz, Kerstin A. [Author]; Bast, Thomas [Author]; Dietel, Tobias [Author]; Korenke, G. Christoph [Author]; Christoph, Sophie [Author]; Brennenstuhl, Heiko [Author]; Rubboli, Guido [Author]; Moller, Rikke S. [Author]; Lesca, Gaetan [Author]; Chaix, Yves [Author]; Kölker, Stefan [Author]; Hoffmann, Georg F. [Author]; Lemke, Johannes R. [Author]; Syrbe, Steffen [Author]

Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

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  • Media type: E-Article
  • Title: Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders
  • Contributor: Döring, Jan H. [Author]; Schröter, Julian [Author]; Jüngling, Jerome [Author]; Biskup, Saskia [Author]; Klotz, Kerstin A. [Author]; Bast, Thomas [Author]; Dietel, Tobias [Author]; Korenke, G. Christoph [Author]; Christoph, Sophie [Author]; Brennenstuhl, Heiko [Author]; Rubboli, Guido [Author]; Moller, Rikke S. [Author]; Lesca, Gaetan [Author]; Chaix, Yves [Author]; Kölker, Stefan [Author]; Hoffmann, Georg F. [Author]; Lemke, Johannes R. [Author]; Syrbe, Steffen [Author]
  • imprint: Basel: MDPI, [2024]
  • Published in: International Journal of Molecular Sciences ; 22, (2021)
  • Language: English
  • Keywords: epilepsy ; epileptic encephalopathy ; shaker ; voltage-gated potassium channel ; ataxia ; Kv1.2
  • Origination:
  • Footnote:
  • Description: 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. Affectedindividuals show early-onset developmental and epileptic encephalopathy, intellectual disability, andmovement disorders resulting from cerebellar dysfunction. In addition, individuals with a mildercourse 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-associateddisorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associatedwith a gain- and loss-of-potassium conductance, more often show early developmental abnormalitiesand 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 KCNA2variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights theimportance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 asa mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinicalspectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum,genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants.
  • Access State: Open Access
  • Rights information: Attribution (CC BY)