Journal Article

Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy

Ishiura, Hiroyuki, Kondo, Takayuki, Ohsawa-Yoshida, Natsumi, Yasuda, Takeshi, Ishiura, Shoichi, Ichikawa, Yaeko, Date, Hidetoshi, Yamasaki, Ryo, Koh, Kishin, Onodera, Osamu, Yurino, Hideaki, Hanajima, Ritsuko, Kaida, Ken-ichi, Sakiyama, Yoshio, Toyoshima, Yasuko, Hayashi, Toshihiro, Takiyama, Yoshihisa, Ikeda, Akio, Goto, Jun, Sasagawa, Mutsuo, Morishita, Shinichi, Shimizu, Jun, Higashihara, Mana, Abe, Koji, Nishizawa, Masatoyo, Kubota, Akatsuki, Tada, Masayoshi, Saito, Yutaka, Hamada, Masashi, Kanesawa, Norio, Kuroha, Yasuko, Yoshimura, Jun, Suzuki, Yutaka, Hasegawa, Naoya, Mitsui, Jun, Shibata, Shota, Tamaoka, Akira, Higasa, Koichiro, Sano, Akira, Matsukawa, Takashi, Otsuka, Mieko, Akiyama, Hiroshi, Nakamura, Masayuki, Kakita, Akiyoshi, Doi, Koichiro, Takahashi, Yuji, Shirota, Yuichiro, Takahashi, Hitoshi, Ichikawa, Kazuki, Sanpei, Kazuhiro, Nakamoto, Fumiko Kusunoki, Inomata-Terada, Satomi, Koike, Ryoko, Hitomi, Takefumi, Ueki, Akira, Tanaka, Masaki, Matsukawa, Miho Kawabe, Mitsue, Aki, Sugano, Sumio, Fujiyama, Asao, Terao, Yasuo, Tsuji, Shoji, Otsuki, Taisuke, Takano, Hiroki, Qu, Wei, Kanda, Junko, Ugawa, Yoshi

2018

Overview

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. This study identifies TTTCA- and TTTTA-repeat expansions in benign adult familial myoclonic epilepsy. Cortical neurons from affected people exhibit RNA foci containing these expanded repeats, suggesting RNA toxicity as the mechanism underlying disease pathogenesis.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 38/32 / 45 / 45/77 / 631/208/207 / 631/378 / 692/699/375/178 / 82 / 82/1 / Adult / Age of Onset / Agriculture / Animal Genetics and Genomics / Ataxia / Autoantigens - genetics / Bacterial artificial chromosomes / Base Sequence / Benign / Bioinformatics / Biomedical and Life Sciences / Biomedicine / Cancer Research / Deoxyribonucleic acid / Disease / DNA / DNA Repeat Expansion / DNA sequencing / Epilepsies, Myoclonic - etiology / Epilepsies, Myoclonic - genetics / Epilepsies, Myoclonic - pathology / Epilepsy / Female / Gene Function / Genes / Genomes / Genomic Instability / Genomics / Guanine Nucleotide Exchange Factors - genetics / Haplotypes / Human Genetics / Humans / Introns / Ion channels / Male / Microsatellite Repeats / Mutation / Nerve Tissue Proteins - genetics / Neurological diseases / Neurotransmitter receptors / Neurotransmitters / Pathogenesis / Patients / Pedigree / Porosity / Purkinje Cells - pathology / Receptors / RNA-Binding Proteins - genetics / Sequence Analysis, DNA / Sterile Alpha Motif - genetics / Tremor