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

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

doi:10.1038/s41588-018-0067-2

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

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

Department of Neurogy

Research output: Contribution to journal › Article › peer-review

194 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	581-590
Number of pages	10
Journal	Nature genetics
Volume	50
Issue number	4
DOIs	https://doi.org/10.1038/s41588-018-0067-2
Publication status	Published - Apr 1 2018

All Science Journal Classification (ASJC) codes

Genetics

Access to Document

10.1038/s41588-018-0067-2

Cite this

Ishiura, H., Doi, K., Mitsui, J., Yoshimura, J., Matsukawa, M. K., Fujiyama, A., Toyoshima, Y., Kakita, A., Takahashi, H., Suzuki, Y., Sugano, S., Qu, W., Ichikawa, K., Yurino, H., Higasa, K., Shibata, S., Mitsue, A., Tanaka, M., Ichikawa, Y., ... Tsuji, S. (2018). Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy. Nature genetics, 50(4), 581-590. https://doi.org/10.1038/s41588-018-0067-2

Ishiura, H, Doi, K, Mitsui, J, Yoshimura, J, Matsukawa, MK, Fujiyama, A, Toyoshima, Y, Kakita, A, Takahashi, H, Suzuki, Y, Sugano, S, Qu, W, Ichikawa, K, Yurino, H, Higasa, K, Shibata, S, Mitsue, A, Tanaka, M, Ichikawa, Y, Takahashi, Y, Date, H, Matsukawa, T, Kanda, J, Nakamoto, FK, Higashihara, M, Abe, K, Koike, R, Sasagawa, M, Kuroha, Y, Hasegawa, N, Kanesawa, N, Kondo, T, Hitomi, T, Tada, M, Takano, H, Saito, Y, Sanpei, K, Onodera, O, Nishizawa, M, Nakamura, M, Yasuda, T, Sakiyama, Y, Otsuka, M, Ueki, A, Kaida, KI, Shimizu, J, Hanajima, R, Hayashi, T, Terao, Y, Inomata-Terada, S, Hamada, M, Shirota, Y, Kubota, A, Ugawa, Y, Koh, K, Takiyama, Y, Ohsawa-Yoshida, N, Ishiura, S, Yamasaki, R, Tamaoka, A, Akiyama, H, Otsuki, T, Sano, A, Ikeda, A, Goto, J, Morishita, S & Tsuji, S 2018, 'Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy', Nature genetics, vol. 50, no. 4, pp. 581-590. https://doi.org/10.1038/s41588-018-0067-2

@article{ffea34161a744e07a634bffd32b05b35,

title = "Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy",

abstract = "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.",

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

note = "Funding Information: We thank the patients and family members for participating in the study. We thank T. Sekiya (Department of Neurology, Sumitomo Hospital, Osaka, Japan), M. Kinoshita (Department of Neurology, Utano National Hospital, National Hospital Organization, Kyoto, Japan), M. Kanda (Department of Neurology, Ijinkai Takeda General Hospital, Kyoto, Japan), K. Hokkoku (Department of Neurology, Teikyo University School of Medicine, Tokyo, Japan) and others for kindly collecting and providing clinical information, and K. Hirayama, Zhenghong Wu, M. Takeyama, K. Wakabayashi, N. Maruyama, T. Sugai, and Y. Tsukamoto for technical support. This work was supported in part by KAKENHI (Grants-in-Aid for Scientific Research on Innovative Areas 22129001 and 22129002) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Grants-in-Aid (H23-Jitsuyoka (Nanbyo)-Ippan-004 and H26-Jitsuyoka (Nanbyo)-Ippan-080) from the Ministry of Health, Welfare and Labour, Japan, and grants (15ek0109065h0002, 16kk0205001h0001, 17kk0205001h0002 and 17ek0109279h0001) from the Japan Agency for Medical Research and Development (AMED) to S.T. This work was also supported by KAKENHI (Grant-in-Aid for Young Scientists 17H05085) from the Japan Society for the Promotion of Science for H.I. Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = apr,

day = "1",

doi = "10.1038/s41588-018-0067-2",

language = "English",

volume = "50",

pages = "581--590",

journal = "Nature genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "4",

}

TY - JOUR

T1 - Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy

AU - Ishiura, Hiroyuki

AU - Doi, Koichiro

AU - Mitsui, Jun

AU - Yoshimura, Jun

AU - Matsukawa, Miho Kawabe

AU - Fujiyama, Asao

AU - Toyoshima, Yasuko

AU - Kakita, Akiyoshi

AU - Takahashi, Hitoshi

AU - Suzuki, Yutaka

AU - Sugano, Sumio

AU - Qu, Wei

AU - Ichikawa, Kazuki

AU - Yurino, Hideaki

AU - Higasa, Koichiro

AU - Shibata, Shota

AU - Mitsue, Aki

AU - Tanaka, Masaki

AU - Ichikawa, Yaeko

AU - Takahashi, Yuji

AU - Date, Hidetoshi

AU - Matsukawa, Takashi

AU - Kanda, Junko

AU - Nakamoto, Fumiko Kusunoki

AU - Higashihara, Mana

AU - Abe, Koji

AU - Koike, Ryoko

AU - Sasagawa, Mutsuo

AU - Kuroha, Yasuko

AU - Hasegawa, Naoya

AU - Kanesawa, Norio

AU - Kondo, Takayuki

AU - Hitomi, Takefumi

AU - Tada, Masayoshi

AU - Takano, Hiroki

AU - Saito, Yutaka

AU - Sanpei, Kazuhiro

AU - Onodera, Osamu

AU - Nishizawa, Masatoyo

AU - Nakamura, Masayuki

AU - Yasuda, Takeshi

AU - Sakiyama, Yoshio

AU - Otsuka, Mieko

AU - Ueki, Akira

AU - Kaida, Ken Ichi

AU - Shimizu, Jun

AU - Hanajima, Ritsuko

AU - Hayashi, Toshihiro

AU - Terao, Yasuo

AU - Inomata-Terada, Satomi

AU - Hamada, Masashi

AU - Shirota, Yuichiro

AU - Kubota, Akatsuki

AU - Ugawa, Yoshikazu

AU - Koh, Kishin

AU - Takiyama, Yoshihisa

AU - Ohsawa-Yoshida, Natsumi

AU - Ishiura, Shoichi

AU - Yamasaki, Ryo

AU - Tamaoka, Akira

AU - Akiyama, Hiroshi

AU - Otsuki, Taisuke

AU - Sano, Akira

AU - Ikeda, Akio

AU - Goto, Jun

AU - Morishita, Shinichi

AU - Tsuji, Shoji

N1 - Funding Information: We thank the patients and family members for participating in the study. We thank T. Sekiya (Department of Neurology, Sumitomo Hospital, Osaka, Japan), M. Kinoshita (Department of Neurology, Utano National Hospital, National Hospital Organization, Kyoto, Japan), M. Kanda (Department of Neurology, Ijinkai Takeda General Hospital, Kyoto, Japan), K. Hokkoku (Department of Neurology, Teikyo University School of Medicine, Tokyo, Japan) and others for kindly collecting and providing clinical information, and K. Hirayama, Zhenghong Wu, M. Takeyama, K. Wakabayashi, N. Maruyama, T. Sugai, and Y. Tsukamoto for technical support. This work was supported in part by KAKENHI (Grants-in-Aid for Scientific Research on Innovative Areas 22129001 and 22129002) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Grants-in-Aid (H23-Jitsuyoka (Nanbyo)-Ippan-004 and H26-Jitsuyoka (Nanbyo)-Ippan-080) from the Ministry of Health, Welfare and Labour, Japan, and grants (15ek0109065h0002, 16kk0205001h0001, 17kk0205001h0002 and 17ek0109279h0001) from the Japan Agency for Medical Research and Development (AMED) to S.T. This work was also supported by KAKENHI (Grant-in-Aid for Young Scientists 17H05085) from the Japan Society for the Promotion of Science for H.I. Publisher Copyright: © 2018 The Author(s).

PY - 2018/4/1

Y1 - 2018/4/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85042885009&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85042885009&partnerID=8YFLogxK

U2 - 10.1038/s41588-018-0067-2

DO - 10.1038/s41588-018-0067-2

M3 - Article

C2 - 29507423

AN - SCOPUS:85042885009

SN - 1061-4036

VL - 50

SP - 581

EP - 590

JO - Nature genetics

JF - Nature genetics

IS - 4

ER -

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

Abstract

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this