Variant Intestinal-Cell Kinase in Juvenile Myoclonic Epilepsy
Variant Intestinal-Cell Kinase in Juvenile Myoclonic Epilepsy
复制标题
DOI：
10.1056/nejmoa1700175
复制
发表时间：
2018-03-15
影响因子：
158.5
通讯作者：
Delgado-Escueta, A. V.
中科院分区：
文献类型：
--
作者：
Bailey, J. N.;de Nijs, L.;Delgado-Escueta, A. V.
背景在青少年肌阵挛性癫痫中，脑电图（EEG）上弥漫性多尖峰促进惊厥的网络的遗传基础以及称为微发育不良的微妙微观脑发育不良的数据有限。方法使用桑格测序，我们对一个患有青少年肌阵挛性癫痫的大家族的六名成员的外显子组进行了测序，并证实了这一点。 所有 37 名家庭成员均处于同隔离状态。我们对另外 310 名患有这种疾病的患者进行了 DNA 熔解曲线分析和编码肠细胞激酶 (ICK) 基因的靶向实时 DNA 测序的变异筛查。我们计算了共分离变异的贝叶斯对数赔率 (LOD) 分数、病例对照关联中的赔率比以及基因组聚合数据库中的等位基因频率。我们在体外对变异体对有丝分裂、细胞凋亡和放射状神经母细胞迁移的影响进行了功能测试，并在缺乏 Ick.RESULTSA 副本的小鼠中进行了视频脑电图研究。RESULTSA 变异体 K305T (c.914A -> C) 在 12 名青少年肌阵挛性癫痫家族成员的脑电图上与癫痫或多尖峰共分离。我们在另外 310 名患者中的 22 名 (7%) 中发现了 21 种致病性 ICK 变异。四种强连锁变体（K220E、K305T、A615T 和 R632X）损害有丝分裂、细胞周期退出和放射状神经母细胞迁移，同时促进细胞凋亡。在异氟醚麻醉的浅睡眠期间，脑电图上类似于人类青少年肌阵挛性癫痫发作的强直阵挛性惊厥和多尖峰在敲除杂合子小鼠中比在野生型小鼠中更常见（P = 0.02）。 结论我们的数据提供了证据，表明 ICK 杂合子变异导致 7% 的青少年肌阵挛性癫痫 患者纳入我们的分析。变异ICK影响细胞过程，有助于解释青少年肌阵挛性癫痫脑电图上观察到的微发育障碍和多尖峰网络。
BACKGROUNDIn juvenile myoclonic epilepsy, data are limited on the genetic basis of networks promoting convulsions with diffuse polyspikes on electroencephalography (EEG) and the subtle microscopic brain dysplasia called microdysgenesis.METHODSUsing Sanger sequencing, we sequenced the exomes of six members of a large family affected with juvenile myoclonic epilepsy and confirmed cosegregation in all 37 family members. We screened an additional 310 patients with this disorder for variants on DNA melting-curve analysis and targeted real-time DNA sequencing of the gene encoding intestinal-cell kinase (ICK). We calculated Bayesian logarithm of the odds (LOD) scores for cosegregating variants, odds ratios in case-control associations, and allele frequencies in the Genome Aggregation Database. We performed functional tests of the effects of variants on mitosis, apoptosis, and radial neuroblast migration in vitro and conducted video-EEG studies in mice lacking a copy of Ick.RESULTSA variant, K305T (c.914A -> C), cosegregated with epilepsy or polyspikes on EEG in 12 members of the family affected with juvenile myoclonic epilepsy. We identified 21 pathogenic ICK variants in 22 of 310 additional patients (7%). Four strongly linked variants (K220E, K305T, A615T, and R632X) impaired mitosis, cell-cycle exit, and radial neuroblast migration while promoting apoptosis. Tonic-clonic convulsions and polyspikes on EEG resembling seizures in human juvenile myoclonic epilepsy occurred more often in knockout heterozygous mice than in wildtype mice (P = 0.02) during light sleep with isoflurane anesthesia.CONCLUSIONSOur data provide evidence that heterozygous variants in ICK caused juvenile myoclonic epilepsy in 7% of the patients included in our analysis. Variant ICK affects cell processes that help explain microdysgenesis and polyspike networks observed on EEG in juvenile myoclonic epilepsy.