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Mov Disord. 2016 Nov;31(11):1743-1748. doi: 10.1002/mds.26737. Epub 2016 Aug 1.

Dominant-negative mutation p.Arg324Thr in KCNA1 impairs Kv1.1 channel function in episodic ataxia.

Author information

1
Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
2
Departamento de Fisiología Médica y Biofísica, Universidad de Sevilla, Sevilla, Spain.
3
Grup de Recerca en Neurologia Infantil, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
4
Servicio de Pediatría, Neuropediatría, Hospital Universitario Puerta de Hierro, Majadahonda, Madrid, Spain.
5
Servicio de Biología Molecular, Hospital Universitario Virgen Macarena, Facultad de Medicina, Sevilla, Spain.

Abstract

BACKGROUND:

Episodic ataxia type 1 is a rare autosomal dominant neurological disorder caused by mutations in the KCNA1 gene that encodes the α subunit of voltage-gated potassium channel Kv1.1. The functional consequences of identified mutations on channel function do not fully correlate with the clinical phenotype of patients.

METHODS:

A clinical and genetic study was performed in a family with 5 patients with episodic ataxia type 1, with concurrent epilepsy in 1 of them. Protein expression, modeling, and electrophysiological analyses were performed to study Kv1.1 function.

RESULTS:

Whole-genome linkage and candidate gene analyses revealed the novel heterozygous mutation p.Arg324Thr in the KCNA1 gene. The encoded mutant Kv1.1 channel displays reduced currents and altered activation and inactivation.

CONCLUSIONS:

Taken together, we provide genetic and functional evidence that mutation p.Arg324Thr in the KCNA1 gene is pathogenic and results in episodic ataxia type 1 through a dominant-negative effect. © 2016 International Parkinson and Movement Disorder Society.

KEYWORDS:

KCNA1; Kv1.1; electrophysiology; episodic ataxia; mutation

PMID:
27477325
DOI:
10.1002/mds.26737
[Indexed for MEDLINE]

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