SCN4A pore mutation pathogenetically contributes to autosomal dominant essential tremor and may increase susceptibility to epilepsy

被引:39
作者
Bergareche, Alberto [1 ,2 ,4 ]
Bednarz, Marcin [5 ]
Sanchez, Elena [6 ]
Krebs, Catharine E. [6 ]
Ruiz-Martinez, Javier [1 ,2 ,4 ]
De La Riva, Patricia [1 ,2 ,4 ]
Makarov, Vladimir [11 ]
Gorostidi, Ana [1 ,2 ,4 ]
Jurkat-Rott, Karin [5 ]
Felix Marti-Masso, Jose [1 ,2 ,3 ,4 ]
Paisan-Ruiz, Coro [6 ,7 ,8 ,9 ,10 ]
机构
[1] Hosp Univ Donostia, Dept Neurol, Movement Disorders Unit, San Sebastian, Guipuzcoa, Spain
[2] Univ Basque Country, UPV EHU, Area Neurosci, Biodonostia Res Inst, San Sebastian, Gipuzkoa, Spain
[3] Univ Basque Country, UPV EHU, Dept Neurosci, San Sebastian, Gipuzkoa, Spain
[4] Carlos III Hlth Inst, Ctr Invest Biomed Red Enfermedades Neurodegenerat, Madrid, Spain
[5] Univ Ulm, Div Neurophysiol, D-89070 Ulm, Germany
[6] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA
[7] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA
[8] Icahn Sch Med Mt Sinai, Dept Genet & Genom Sci, New York, NY 10029 USA
[9] Icahn Sch Med Mt Sinai, Friedman Brain Inst, New York, NY 10029 USA
[10] Icahn Sch Med Mt Sinai, Mindich Child Hlth & Dev Inst, New York, NY 10029 USA
[11] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA
基金
美国国家卫生研究院;
关键词
SODIUM-CHANNEL; PARKINSONS-DISEASE; PERIODIC PARALYSIS; COMMON; DYSFUNCTION; MECHANISMS; GENETICS; FAMILY; BLOCK;
D O I
10.1093/hmg/ddv410
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:7111 / 7120
页数:10
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