2. Academic Validation
  3. 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

  • Nat Genet. 2018 Apr;50(4):581-590. doi: 10.1038/s41588-018-0067-2.
Hiroyuki Ishiura 1,  Koichiro Doi 2,  Jun Mitsui 1,  Jun Yoshimura 2,  Miho Kawabe Matsukawa 1,  Asao Fujiyama 3,  Yasuko Toyoshima 4,  Akiyoshi Kakita 4,  Hitoshi Takahashi 4,  Yutaka Suzuki 2,  Sumio Sugano 5,  Wei Qu 2,  Kazuki Ichikawa 2,  Hideaki Yurino 6,  Koichiro Higasa 7,  Shota Shibata 1,  Aki Mitsue 1,  Masaki Tanaka 1,  Yaeko Ichikawa 8,  Yuji Takahashi 9,  Hidetoshi Date 1,  Takashi Matsukawa 1,  Junko Kanda 1,  Fumiko Kusunoki Nakamoto 1,  Mana Higashihara 10,  Koji Abe 11,  Ryoko Koike 12,  Mutsuo Sasagawa 13,  Yasuko Kuroha 12,  Naoya Hasegawa 14,  Norio Kanesawa 15,  Takayuki Kondo 16,  Takefumi Hitomi 16 17,  Masayoshi Tada 18,  Hiroki Takano 19,  Yutaka Saito 20,  Kazuhiro Sanpei 21,  Osamu Onodera 18,  Masatoyo Nishizawa 22,  Masayuki Nakamura 23,  Takeshi Yasuda 24,  Yoshio Sakiyama 25,  Mieko Otsuka 26,  Akira Ueki,  Ken-Ichi Kaida 27,  Jun Shimizu 1,  Ritsuko Hanajima 28,  Toshihiro Hayashi 1,  Yasuo Terao 29,  Satomi Inomata-Terada 1,  Masashi Hamada 1,  Yuichiro Shirota 1,  Akatsuki Kubota 1,  Yoshikazu Ugawa 30,  Kishin Koh 31,  Yoshihisa Takiyama 31,  Natsumi Ohsawa-Yoshida 32,  Shoichi Ishiura 32 33,  Ryo Yamasaki 34,  Akira Tamaoka 35,  Hiroshi Akiyama 36,  Taisuke Otsuki 37,  Akira Sano 23,  Akio Ikeda 38,  Jun Goto 39,  Shinichi Morishita 2,  Shoji Tsuji 40 41 42
Affiliations

Affiliations

  • 1 Department of Neurology, The University of Tokyo Hospital, Tokyo, Japan.
  • 2 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan.
  • 3 Advanced Genomics Center, National Institute of Genetics, Shizuoka, Japan.
  • 4 Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan.
  • 5 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
  • 6 Department of Laboratory Medicine, Graduate School of Medical Sciences, Kanazawa University, Ishikawa, Japan.
  • 7 Human Disease Genomics, Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • 8 Department of Neurology, Kyorin University, Tokyo, Japan.
  • 9 Department of Neurology, National Center of Neurology and Psychiatry, Tokyo, Japan.
  • 10 Department of Neurology, Tokyo Metropolitan Geriatric Hospital, Tokyo, Japan.
  • 11 Department of Neurology, Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
  • 12 Department of Neurology, Nishi-Niigata Chuo National Hospital, Niigata, Japan.
  • 13 Department of Psychiatry, Toyosato Hospital, Ibaraki, Japan.
  • 14 Department of Epilepsy, Nishi-Niigata Chuo National Hospital, Niigata, Japan.
  • 15 Division of Cardiology, National Hospital Organization Takasaki General Medical Center, Gunma, Japan.
  • 16 Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • 17 Department of Clinical Laboratory Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • 18 Department of Neurology, Brain Research Institute, Niigata University, Niigata, Japan.
  • 19 Department of Neurology, Tachikawa General Hospital, Niigata, Japan.
  • 20 Department of Neurology, Sannocho Hospital, Niigata, Japan.
  • 21 Department of Neurology, Sado General Hospital, Niigata, Japan.
  • 22 Department of Neurology, Niigata Medical Center, Niigata, Japan.
  • 23 Department of Psychiatry, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
  • 24 Department of Neurology, Kurashikikinen Hospital, Okayama, Japan.
  • 25 Department of Neurology, Jichi Medical University, Saitama Medical Center, Saitama, Japan.
  • 26 Department of Neurology, International University of Health and Welfare, Tochigi, Japan.
  • 27 Third Department of Internal Medicine, National Defense Medical College, Saitama, Japan.
  • 28 Department of Neurology, School of Medicine, Kitasato University, Kanagawa, Japan.
  • 29 Department of Cell Physiology, School of Medicine, Kyorin University, Tokyo, Japan.
  • 30 Department of Neurology, Fukushima Medical University, Fukushima, Japan.
  • 31 Department of Neurology, University of Yamanashi, Yamanashi, Japan.
  • 32 Department of Life Sciences, Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan.
  • 33 Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan.
  • 34 Department of Neurology, Neurological Institute, Faculty of Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • 35 Department of Neurology, Faculty of Medicine, University of Tsukuba, Ibaraki, Japan.
  • 36 Hiratsuka Hospital, Kanagawa, Japan.
  • 37 Epilepsy Hospital Bethel Japan, Miyagi, Japan.
  • 38 Department of Epilepsy, Movement Disorders and Physiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • 39 Department of Neurology, International University of Health and Welfare Mita Hospital, Tokyo, Japan.
  • 40 Department of Neurology, The University of Tokyo Hospital, Tokyo, Japan. [email protected].
  • 41 Medical Genome Center, The University of Tokyo Hospital, Tokyo, Japan. [email protected].
  • 42 International University of Health and Welfare, Chiba, Japan. [email protected].
PMID: 29507423 DOI: 10.1038/s41588-018-0067-2
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.

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