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

doi:10.1038/s41588-018-0067-2

. 2018 Apr;50(4):581-590.

doi: 10.1038/s41588-018-0067-2. Epub 2018 Mar 5.

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

Hiroyuki Ishiura¹, Koichiro Doi², Jun Mitsui¹, Jun Yoshimura², Miho Kawabe Matsukawa¹, Asao Fujiyama³, Yasuko Toyoshima⁴, Akiyoshi Kakita⁴, Hitoshi Takahashi⁴, Yutaka Suzuki², Sumio Sugano⁵, Wei Qu², Kazuki Ichikawa², Hideaki Yurino⁶, Koichiro Higasa⁷, Shota Shibata¹, Aki Mitsue¹, Masaki Tanaka¹, Yaeko Ichikawa⁸, Yuji Takahashi⁹, Hidetoshi Date¹, Takashi Matsukawa¹, Junko Kanda¹, Fumiko Kusunoki Nakamoto¹, Mana Higashihara¹⁰, Koji Abe¹¹, Ryoko Koike¹², Mutsuo Sasagawa¹³, Yasuko Kuroha¹², Naoya Hasegawa¹⁴, Norio Kanesawa¹⁵, Takayuki Kondo¹⁶, Takefumi Hitomi^{16

17}, Masayoshi Tada¹⁸, Hiroki Takano¹⁹, Yutaka Saito²⁰, Kazuhiro Sanpei²¹, Osamu Onodera¹⁸, Masatoyo Nishizawa²², Masayuki Nakamura²³, Takeshi Yasuda²⁴, Yoshio Sakiyama²⁵, Mieko Otsuka²⁶, Akira Ueki, Ken-Ichi Kaida²⁷, Jun Shimizu¹, Ritsuko Hanajima²⁸, Toshihiro Hayashi¹, Yasuo Terao²⁹, Satomi Inomata-Terada¹, Masashi Hamada¹, Yuichiro Shirota¹, Akatsuki Kubota¹, Yoshikazu Ugawa³⁰, Kishin Koh³¹, Yoshihisa Takiyama³¹, Natsumi Ohsawa-Yoshida³², Shoichi Ishiura^{32

33}, Ryo Yamasaki³⁴, Akira Tamaoka³⁵, Hiroshi Akiyama³⁶, Taisuke Otsuki³⁷, Akira Sano²³, Akio Ikeda³⁸, Jun Goto³⁹, Shinichi Morishita², Shoji Tsuji^{40

41

42}

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

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

Hiroyuki Ishiura et al. Nat Genet. 2018 Apr.

. 2018 Apr;50(4):581-590.

doi: 10.1038/s41588-018-0067-2. Epub 2018 Mar 5.

Authors

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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Comment in

Epilepsy: A role for expanded DNA repeats in familial epilepsy.
Wood H. Wood H. Nat Rev Neurol. 2018 May;14(5):251. doi: 10.1038/nrneurol.2018.37. Epub 2018 Mar 23. Nat Rev Neurol. 2018. PMID: 29569625 No abstract available.
Repeat expansions in myoclonic epilepsy.
van Blitterswijk M, Rademakers R. van Blitterswijk M, et al. Nat Genet. 2018 Apr;50(4):477-478. doi: 10.1038/s41588-018-0093-0. Nat Genet. 2018. PMID: 29632377 No abstract available.
The Key to FAME: Intronic Repeat Expansions Cause Human Epilepsies.
Scheffer IE. Scheffer IE. Epilepsy Curr. 2018 Jul-Aug;18(4):238-239. doi: 10.5698/1535-7597.18.4.238. Epilepsy Curr. 2018. PMID: 30254519 Free PMC article. No abstract available.

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References

1. Inazuki, G. et al. A clinical study and neuropathological findings of a familial disease with myoclonus and epilepsy–the nosological place of familial essential myoclonus and epilepsy (FEME). Psych. Neurol. Jpn. 92, 1–21 (1990).
1. Ikeda, A. et al. Cortical tremor: a variant of cortical reflex myoclonus. Neurology 40, 1561–1565 (1990). - PubMed
1. Yasuda, T. Benign adult familial myoclonic epilepsy (BAFME). Kawasaki Med. J. 17, 1–13 (1991).
1. Plaster, N. M. et al. Genetic localization of the familial adult myoclonic epilepsy (FAME) gene to chromosome 8q24. Neurology 53, 1180–1183 (1999). - PubMed
1. Mikami, M. et al. Localization of a gene for benign adult familial myoclonic epilepsy to chromosome 8q23.3-q24.1. Am. J. Hum. Genet. 65, 745–751 (1999). - PubMed - PMC

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[1] Inazuki, G. et al. A clinical study and neuropathological findings of a familial disease with myoclonus and epilepsy–the nosological place of familial essential myoclonus and epilepsy (FEME). Psych. Neurol. Jpn. 92, 1–21 (1990).

[2] Inazuki, G. et al. A clinical study and neuropathological findings of a familial disease with myoclonus and epilepsy–the nosological place of familial essential myoclonus and epilepsy (FEME). Psych. Neurol. Jpn. 92, 1–21 (1990).

[3] Ikeda, A. et al. Cortical tremor: a variant of cortical reflex myoclonus. Neurology 40, 1561–1565 (1990). - PubMed

[4] Ikeda, A. et al. Cortical tremor: a variant of cortical reflex myoclonus. Neurology 40, 1561–1565 (1990). - PubMed

[5] Yasuda, T. Benign adult familial myoclonic epilepsy (BAFME). Kawasaki Med. J. 17, 1–13 (1991).

[6] Yasuda, T. Benign adult familial myoclonic epilepsy (BAFME). Kawasaki Med. J. 17, 1–13 (1991).

[7] Plaster, N. M. et al. Genetic localization of the familial adult myoclonic epilepsy (FAME) gene to chromosome 8q24. Neurology 53, 1180–1183 (1999). - PubMed

[8] Plaster, N. M. et al. Genetic localization of the familial adult myoclonic epilepsy (FAME) gene to chromosome 8q24. Neurology 53, 1180–1183 (1999). - PubMed

[9] Mikami, M. et al. Localization of a gene for benign adult familial myoclonic epilepsy to chromosome 8q23.3-q24.1. Am. J. Hum. Genet. 65, 745–751 (1999). - PubMed - PMC

[10] Mikami, M. et al. Localization of a gene for benign adult familial myoclonic epilepsy to chromosome 8q23.3-q24.1. Am. J. Hum. Genet. 65, 745–751 (1999). - PubMed - PMC

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

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

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