DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy
DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy
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DOI：
10.1212/wnl.0000000000000488
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发表时间：
2014-06-10
期刊：
影响因子：
9.9
通讯作者：
Baulac, Stephanie
中科院分区：
文献类型：
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作者：
Picard, Fabienne;Makrythanasis, Periklis;Baulac, Stephanie
目的：研究DEPDC 5突变在一系列的30个小的欧洲家庭与常染色体显性遗传夜间额叶癫痫（ADNFLE）的表型兼容的患病率。方法：30个无关的家庭与ADNFLE被招募在法国，意大利，德国，比利时和挪威。在10个先证者中进行全外显子组测序，在20个先证者中进行DEPDC 5编码序列的直接测序。结果：外显子组测序显示一个德国家系的先证者DEPDC 5基因存在一个剪接受体突变（c.2355-2A>G）。此外，在2个法国和1个比利时家系的先证者中检测到3个DEPDC 5无义突变（p.Arg487*、p.Arg1087* 和p.Trp1369*）。无义突变p.Arg487* 和p.Arg1087* 被NMD靶向，导致突变的转录物的降解。在临床水平上，78%的DEPDC 5突变的患者耐药。结论：DEPDC 5功能丧失突变被发现在13%的家庭与ADNFLE的介绍。DEPDC 5突变患者的耐药率高。DEPDC 5突变的小ADNFLE家系可能实际上代表了具有可变病灶表型的更广泛家族性局灶性癫痫的一部分。
Objective: To study the prevalence of DEPDC5 mutations in a series of 30 small European families with a phenotype compatible with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE).Methods: Thirty unrelated families referred with ADNFLE were recruited in France, Italy, Germany, Belgium, and Norway. Whole-exome sequencing was performed in 10 probands and direct sequencing of the DEPDC5 coding sequence in 20 probands. Testing for nonsense-mediated messenger RNA decay (NMD) was performed in lymphoblastic cells.Results: Exome sequencing revealed a splice acceptor mutation (c.2355-2A>G) in DEPDC5 in the proband of aGerman family. In addition, 3 nonsense DEPDC5 mutations (p.Arg487*, p.Arg1087*, and p.Trp1369*) were detected in the probands of 2 French and one Belgian family. The nonsense mutations p.Arg487* and p.Arg1087* were targeted by NMD, leading to the degradation of the mutated transcripts. At the clinical level, 78% of the patients with DEPDC5 mutations were drug resistant.Conclusions: DEPDC5 loss-of-function mutations were found in 13% of the families with a presentation of ADNFLE. The rate of drug resistance was high in patients with DEPDC5 mutations. Small ADNFLE pedigrees with DEPDC5 mutations might actually represent a part of the broader familial focal epilepsy with variable foci phenotype.