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首页> 外文期刊>Human mutation >A mutation of SCN1B SCN1B associated with GEFS+ causes functional and maturation defects of the voltage‐dependent sodium channel
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A mutation of SCN1B SCN1B associated with GEFS+ causes functional and maturation defects of the voltage‐dependent sodium channel

机译：与GEFS +相关的SCN1B SCN1B的突变导致电压依赖性钠通道的功能和成熟缺陷

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Abstract Voltage‐dependent sodium channels are responsible of the rising phase of the action potential in excitable cells. These integral membrane proteins are composed of a pore‐forming α‐subunit, and one or more auxiliary β subunits. Mutation p.Asp25Asn (D25N; c.73G??A) of the β1 subunit, coded by the gene SCN1B , has been reported in a patient with generalized epilepsy with febrile seizure plus type 1 (GEFS+). In human embryonic kidney 293 (HEK) cells, the heterologous coexpression of D25N‐β1 subunit with Nav1.2, Nav1.4, and Nav1.5 α subunits, representative of brain, skeletal muscle, and heart voltage gated sodium channels, determines a reduced sodium channel functional expression and a negative shift of the activation and inactivation steady state curves. The D25N mutation of the β1 subunit causes a maturation (glycosylation) defect of the protein, leading to a reduced targeting to the plasma membrane. Also the β1‐dependent gating properties of the sodium channels are abolished by the mutation, suggesting that D25N is no more able to interact with the α subunit. Our work underscores the role played by the β1 subunit, highlighting how a defective interaction between the sodium channel constituents could lead to a disabling pathological condition, and opens the possibility to design a mutation‐specific GEFS+ treatment based on protein maturation.
机译：摘要电压依赖性钠通道负责可兴奋细胞动作电位的上升阶段。这些完整的膜蛋白由一个成孔α亚基和一个或多个辅助β亚基组成。据报道，由SCN1B基因编码的β1亚单位的突变p.Asp25Asn（D25N；c.73G？；A）出现在一例全身性癫痫伴热性惊厥加1型（GEFS+）患者中。在人类胚胎肾293（HEK）细胞中，D25N-β1亚基与Nav1的异源共表达。2，导航1。4和导航1。代表大脑、骨骼肌和心脏电压门控钠通道的5α亚单位决定了钠通道功能表达的降低以及激活和失活稳态曲线的负偏移。β1亚单位的D25N突变导致蛋白质的成熟（糖基化）缺陷，导致对质膜的靶向性降低。此外，钠通道的β1依赖性门控特性也因突变而消失，这表明D25N不再能够与α亚单位相互作用。我们的工作强调了β1亚单位所起的作用，强调了钠通道成分之间有缺陷的相互作用如何可能导致致残性病理状态，并为基于蛋白质成熟度设计突变特异性GEFS+治疗开辟了可能性。

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