SCN4A pore mutation pathogenetically contributes to autosomal dominant essential tremor and may increase susceptibility to epilepsy
| Autor: | Coro Paisán-Ruiz, Ana Gorostidi, Elena Sánchez, Catharine E. Krebs, Karin Jurkat-Rott, Alberto Bergareche, Marcin Bednarz, Jose Felix Marti-Masso, Patricia de la Riva, Vladimir Makarov, Javier Ruiz-Martínez |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Essential Tremor Biophysics Biology medicine.disease_cause Epilepsy Mice Genetics medicine Animals Humans Genetic variability Family history NAV1.4 Voltage-Gated Sodium Channel Molecular Biology Genetics (clinical) Exome sequencing Aged Aged 80 and over Mutation Essential tremor Genome Human Periodic paralysis General Medicine Human brain Articles Sequence Analysis DNA Middle Aged medicine.disease medicine.anatomical_structure Female |
| Popis: | Essential tremor (ET) is the most prevalent movement disorder, affecting millions of people in the USA. Although a positive family history is one of the most important risk factors for ET, the genetic causes of ET remain unknown. In an attempt to identify genetic causes for ET, we performed whole-exome sequencing analyses in a large Spanish family with ET, in which two patients also developed epilepsy. To further assess pathogenicity, site-directed mutagenesis, mouse and human brain expression analyses, and patch clamp techniques were performed. A disease-segregating mutation (p.Gly1537Ser) in the SCN4A gene was identified. Posterior functional analyses demonstrated that more rapid kinetics at near-threshold potentials altered ion selectivity and facilitated the conductance of both potassium and ammonium ions, which could contribute to tremor and increase susceptibility to epilepsy, respectively. In this report, for the first time, we associated the genetic variability of SCN4A with the development of essential tremor, which adds ET to the growing list of neurological channelopathies. |
| Databáze: | OpenAIRE |
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