RBFOX1 and RBFOX3 mutations in rolandic epilepsy.
RBFOX1 and RBFOX3 mutations in rolandic epilepsy.
复制标题
DOI：
10.1371/journal.pone.0073323
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Neubauer BA
中科院分区：
文献类型：
--
作者：
Lal D;Reinthaler EM;Altmüller J;Toliat MR;Thiele H;Nürnberg P;Lerche H;Hahn A;Møller RS;Muhle H;Sander T;Zimprich F;Neubauer BA
编码神经元剪接调节因子RBFOX1的基因部分缺失已在一系列神经发育疾病中被报道，包括特发性全身性癫痫。RBFOX1蛋白及其同系物(RBFOX2和RBFOX3)调节许多神经元转录本的选择性剪接，这些转录本参与神经元兴奋性的动态平衡控制。在这项研究中，我们探索了RBFOX1、RBFOX2、RBFOX3基因的结构微缺失和外显子序列变异是否会增加罗兰迪克癫痫(RE)的易感性，这是一种常见的特发性儿童局灶性癫痫。通过对289例无关RE患者的高密度单核苷酸多态性阵列筛查，我们发现了两个半合子缺失，即影响RBFOX1两个非翻译5‘端外显子的365 kb缺失和跨越RBFOX3外显子3的43kb缺失。242例RE患者的外显子组测序发现了RBFOX1的两个新的可能有害的变异，一个移码突变(p.A233Vfs*74)和一个六核苷酸缺失(p.A299_A300del)，以及一个新的RBFOX3无义突变(p.Y287*)。虽然这三个变异是从未受影响的父母那里遗传来的，但在临床或脑电图上表现出RE特征的所有家庭成员中都存在，只有一个例外。相反，在Exome Variant Server数据库中保存的6503名非RE受试者的外显子中没有发现RBFOX1和RBFOX3的有害突变。观察到的RBFOX3外显子3缺失和无义突变表明，RBFOX3是一个新的RE危险因子，表明RBFOX1和RBFOX3的外显子缺失和截断突变是部分和泛发性癫痫综合征的遗传变异的原因。
Partial deletions of the gene encoding the neuronal splicing regulator RBFOX1 have been reported in a range of neurodevelopmental diseases, including idiopathic generalized epilepsy. The RBFOX1 protein and its homologues (RBFOX2 and RBFOX3) regulate alternative splicing of many neuronal transcripts involved in the homeostatic control of neuronal excitability. In this study, we explored if structural microdeletions and exonic sequence variations in RBFOX1, RBFOX2, RBFOX3 confer susceptibility to rolandic epilepsy (RE), a common idiopathic focal childhood epilepsy. By high-density SNP array screening of 289 unrelated RE patients, we identified two hemizygous deletions, a 365 kb deletion affecting two untranslated 5′-terminal exons of RBFOX1 and a 43 kb deletion spanning exon 3 of RBFOX3. Exome sequencing of 242 RE patients revealed two novel probably deleterious variants in RBFOX1, a frameshift mutation (p.A233Vfs*74) and a hexanucleotide deletion (p.A299_A300del), and a novel nonsense mutation in RBFOX3 (p.Y287*). Although the three variants were inherited from unaffected parents, they were present in all family members exhibiting the RE trait clinically or electroencephalographically with only one exception. In contrast, no deleterious mutations of RBFOX1 and RBFOX3 were found in the exomes of 6503 non-RE subjects deposited in the Exome Variant Server database. The observed RBFOX3 exon 3 deletion and nonsense mutation suggest that RBFOX3 represents a novel risk factor for RE, indicating that exon deletions and truncating mutations of RBFOX1 and RBFOX3 contribute to the genetic variance of partial and generalized idiopathic epilepsy syndromes.
登录
查看更多内容
影响因子：
14.9
作者：
通讯作者：
--
影响因子：
3.7
作者：
Dredge BK;Jensen KB
通讯作者：
Jensen KB
影响因子：
3.5
作者：
Bhalla, K;Phillips, HA;Callen, DF
通讯作者：
Callen, DF
影响因子：
4.5
作者：
Damianov, Andrey;Black, Douglas L.
通讯作者：
Black, Douglas L.
影响因子：
5.6
作者：
Doose, H;BriggerHeuer, B;Neubauer, B
通讯作者：
Neubauer, B