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Mutation p.Arg324Thr in the KCNA1 gene alters Kv1.1 channel function in a family with episodic ataxia

AuthorsTristán Clavijo, E. ; Scholl, Francisco G.; Iglesias Escalera, G.; Macaya Ruiz, A.; Martínez Mir, Amalia ; Castellano, Antonio
Issue DateOct-2015
Citation5th Spanish Ion Channel Network Meeting (2015)
AbstractEpisodic ataxia (EA) is a rare autosomal dominant neurological disorder characterized by brief episodes of cerebellar dysfunction and myokymia or neuromyotonia. We recruited the participation of a family with 5 affected members with a diagnosis of paroxysmal kinesigenic dyskinesia vs episodic ataxia with secondarily generalized epilepsy. The age of onset ranged from 3 to 6 years. The patients had brief episodes (<1 min) of choreoathetotic movements of the extremities and trunk, occasional dysarthria, tremor and blurred vision, with no loss of consciousness. Interictal muscle twitching of the hands was observed. Adult patients described an aura-like sensation preceding the episodes. The attacks were triggered by sudden movements, stress and fatigue, among others, and varied in frequency. Carbamazepine partly improved the symptoms, while acetazolamide did not show any effect. We conducted a genome-wide linkage analysis to identify the mutated gene. A maximum LOD score of Z=2.408 was achieved for markers at 2p25.1, 12p13.33-p13.1 and 19q11-q13.42. Sequencing of the KCNA1 gene (12p13.33-p13.1) revealed a novel heterozygous point mutation c.971G>C, p.Arg324Thr. The affected residue is located within the cytoplasmic loop between S4 and S5 of the Kv1.1 channel. The mutation cosegregates with the disease and it is absent from 622 control chromosomes. To study whether the mutation altered the channel biophysical properties, the wild type (WT), heterozygous (WT:R324T) and mutant (R324T) channels were expressed in HEK-293T cells. When compared to the WT channel, the WT:R324T and R324T channels: i) produced significantly smaller currents; ii) activated at more positive potentials (~10 and ~20 mV, respectively) and with significantly slower kinetics; and iii) showed a depolarizing shift (~10 and ~20 mV, respectively) in the voltage dependence of the steady-state inactivation. Taken together, the data reported here support the relevance of the KCNA1 gene in EA and the role of the p.Arg324Thr mutation in the channel kinetics.
DescriptionPóster presentado en la 5th Spanish Ion Channel Network Meeting (RECI V), celebrada en Barcelona del 4 al 6 de octubre de 2015.
Appears in Collections:(IBIS) Comunicaciones congresos
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