Enriqueta Tristán-Clavijo1, Francisco G Scholl1,2, Alfons Macaya3, Gemma Iglesias4, Ana M Rojas1, Miguel Lucas5, Antonio Castellano1,2, Amalia Martinez-Mir1. 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.
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.
Authors: Jenny van der Wijst; Martin Konrad; Sjoerd A J Verkaart; Marcin Tkaczyk; Femke Latta; Janine Altmüller; Holger Thiele; Bodo Beck; Karl Peter Schlingmann; Jeroen H F de Baaij Journal: Nephron Date: 2018-05-23 Impact factor: 2.847
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