De novo gain-of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy.
De novo gain-of-function and loss-of-function mutations of SCN8A in patients with intellectual disabilities and epilepsy.
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DOI：
10.1136/jmedgenet-2014-102813
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发表时间：
2015-05
影响因子：
4
通讯作者：
Kamsteeg EJ
中科院分区：
文献类型：
--
作者：
Blanchard MG;Willemsen MH;Walker JB;Dib-Hajj SD;Waxman SG;Jongmans MC;Kleefstra T;van de Warrenburg BP;Praamstra P;Nicolai J;Yntema HG;Bindels RJ;Meisler MH;Kamsteeg EJ
编码神经元电压门控钠通道NaV1.6的SCN 8A突变与早期婴儿癫痫性脑病13型（EIEE 13）和智力残疾相关。使用临床外显子组测序，我们已经检测到三个新的从头SCN 8A突变的智力残疾患者，和变量的临床特征，包括癫痫发作的两名患者。为了确定这些SCN 8A突变在这三名患者疾病中的因果关系，我们的目的是研究突变钠通道的功能（dys）。在转染细胞中使用电生理学分析评估三种SCN 8A突变的功能后果。这些和其他情况下的基因型-表型相关性与功能分析。第一个突变体显示出10 mV的超极化位移的电压依赖性激活（功能的增益），第二个没有形成功能通道（功能的丧失），而第三个突变是功能上无法区分的野生型通道。 将这些患者的临床特征与文献中的患者进行比较表明，功能获得性突变与严重EIEE相关，而杂合功能丧失性突变导致伴有或不伴有癫痫发作的智力残疾。这些数据表明，通过临床外显子组测序检测到的错义突变的功能分析，无论是遗传的还是从头的，对于大规模平行测序时代的临床解释是有价值的。
Mutations of SCN8A encoding the neuronal voltage-gated sodium channel NaV1.6 are associated with early-infantile epileptic encephalopathy type 13 (EIEE13) and intellectual disability. Using clinical exome sequencing, we have detected three novel de novo SCN8A mutations in patients with intellectual disabilities, and variable clinical features including seizures in two patients. To determine the causality of these SCN8A mutations in the disease of those three patients, we aimed to study the (dys)function of the mutant sodium channels. The functional consequences of the three SCN8A mutations were assessed using electrophysiological analyses in transfected cells. Genotype–phenotype correlations of these and other cases were related to the functional analyses. The first mutant displayed a 10 mV hyperpolarising shift in voltage dependence of activation (gain of function), the second did not form functional channels (loss of function), while the third mutation was functionally indistinguishable from the wildtype channel. Comparison of the clinical features of these patients with those in the literature suggests that gain-of-function mutations are associated with severe EIEE, while heterozygous loss-of-function mutations cause intellectual disability with or without seizures. These data demonstrate that functional analysis of missense mutations detected by clinical exome sequencing, both inherited and de novo, is valuable for clinical interpretation in the age of massive parallel sequencing.
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影响因子：
3.5
作者：
Ogiwara I;Iwasato T;Miyamoto H;Iwata R;Yamagata T;Mazaki E;Yanagawa Y;Tamamaki N;Hensch TK;Itohara S;Yamakawa K
通讯作者：
Yamakawa K
影响因子：
3.8
作者：
Ceulemans, BPGM;Claes, LRF;Lagae, LG
通讯作者：
Lagae, LG
影响因子：
2.9
作者：
Klein, JP;Khera, DS;Blumenfeld, H
通讯作者：
Blumenfeld, H
影响因子：
2.5
作者：
Levin, Stephen I.;Khaliq, Zayd M.;Meisler, Miriam H.
通讯作者：
Meisler, Miriam H.
影响因子：
5.8
作者：
Larkin, M. A.;Blackshields, G.;Higgins, D. G.
通讯作者：
Higgins, D. G.