Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy
Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy
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DOI：
10.1038/s41588-018-0067-2
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发表时间：
2018-04-01
期刊：
影响因子：
30.8
通讯作者：
Tsuji, Shoji
中科院分区：
文献类型：
--
作者：
Ishiura, Hiroyuki;Doi, Koichiro;Tsuji, Shoji
癫痫是一种常见的神经系统疾病，编码离子通道或神经递质受体的基因突变是单基因形式癫痫的常见原因。在这里，我们表明，TTTCA和TTTTA重复序列在SAMD12的内含子4的异常扩展导致良性成人家族性肌阵挛性癫痫（BAFME）。BAC克隆的单分子实时测序和基因组DNA的纳米孔测序鉴定了SAMD12中的两种重复构型。有趣的是，在两个临床诊断为BAFME的家族中，没有观察到SAMD12中的重复扩增，我们在TNRC6A和RAPGEF 2的内含子中鉴定了TTTCA和TTTTA重复的相似扩增，表明相同重复基序的扩增参与了BAFME的发病机制，而不管扩增的重复位于哪个基因中。非编码重复序列的扩增导致肌阵挛性震颤和癫痫的神经元功能障碍，这一发现扩展了对此类重复序列扩增疾病的理解。
Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.