Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease

doi:10.1038/s41588-019-0459-y

. 2019 Aug;51(8):1215-1221.

doi: 10.1038/s41588-019-0459-y. Epub 2019 Jul 22.

Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease

Jun Sone^{1

2}, Satomi Mitsuhashi³, Atsushi Fujita³, Takeshi Mizuguchi³, Kohei Hamanaka³, Keiko Mori⁴, Haruki Koike¹, Akihiro Hashiguchi⁵, Hiroshi Takashima⁵, Hiroshi Sugiyama⁶, Yutaka Kohno⁷, Yoshihisa Takiyama⁸, Kengo Maeda⁹, Hiroshi Doi¹⁰, Shigeru Koyano¹⁰, Hideyuki Takeuchi¹⁰, Michi Kawamoto¹¹, Nobuo Kohara¹¹, Tetsuo Ando¹², Toshiaki Ieda¹³, Yasushi Kita¹⁴, Norito Kokubun¹⁵, Yoshio Tsuboi¹⁶, Kazutaka Katoh^{17

18}, Yoshihiro Kino¹⁹, Masahisa Katsuno¹, Yasushi Iwasaki²⁰, Mari Yoshida²⁰, Fumiaki Tanaka¹⁰, Ikuo K Suzuki²¹, Martin C Frith^{18

22

23}, Naomichi Matsumoto²⁴, Gen Sobue^{25

26

27}

Affiliations

¹ Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
² Department of Neurology, National hospital organization Suzuka National Hospital, Suzuka, Japan.
³ Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
⁴ Department of Neurology, Oyamada Memorial Spa Hospital, Yokkaichi, Japan.
⁵ Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
⁶ Department of Neurology, National Hospital Organization Utano National Hospital, Kyoto, Japan.
⁷ Department of Neurology, Ibaraki Prefectural University of Health Sciences, Ibaraki, Japan.
⁸ Department of Neurology, University of Yamanashi, Chuo, Yamanashi, Japan.
⁹ Department of Neurology, National hospital organization Higashi-Ohmi General Medical Center, Higashi-Ohmi, Japan.
¹⁰ Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
¹¹ Department of Neurology, Kobe City Medical Center General Hospital, Kobe, Japan.
¹² Department of Neurology, Anjo Kosei Hospital, Anjo, Japan.
¹³ Department of Neurology, Yokkaichi Municipal Hospital, Yokkaichi, Japan.
¹⁴ Department of Neurology, Hyogo Brain and Heart Center, Himeji, Japan.
¹⁵ Department of Neurology, Dokkyo Medical University, Tochigi, Japan.
¹⁶ Department of Neurology, Fukuoka University, Fukuoka, Japan.
¹⁷ Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
¹⁸ Artificial Intelligence Research Center, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
¹⁹ Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Tokyo, Japan.
²⁰ Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan.
²¹ Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
²² Graduate School of Frontier Sciences, University of Tokyo, Chiba, Japan.
²³ Computational Bio Big-Data Open Innovation Laboratory, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
²⁴ Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. naomat@yokohama-cu.ac.jp.
²⁵ Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan. sobueg@med.nagoya-u.ac.jp.
²⁶ Department of Neurology, and Brain and Mind Research Center, Nagoya University Graduate School of Medicine, Nagoya, Japan. sobueg@med.nagoya-u.ac.jp.
²⁷ Aichi Medical University, Nagakute, Aichi, Japan. sobueg@med.nagoya-u.ac.jp.

PMID: 31332381
DOI: 10.1038/s41588-019-0459-y

Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease

Jun Sone et al. Nat Genet. 2019 Aug.

. 2019 Aug;51(8):1215-1221.

doi: 10.1038/s41588-019-0459-y. Epub 2019 Jul 22.

Authors

Affiliations

¹ Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
² Department of Neurology, National hospital organization Suzuka National Hospital, Suzuka, Japan.
³ Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
⁴ Department of Neurology, Oyamada Memorial Spa Hospital, Yokkaichi, Japan.
⁵ Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
⁶ Department of Neurology, National Hospital Organization Utano National Hospital, Kyoto, Japan.
⁷ Department of Neurology, Ibaraki Prefectural University of Health Sciences, Ibaraki, Japan.
⁸ Department of Neurology, University of Yamanashi, Chuo, Yamanashi, Japan.
⁹ Department of Neurology, National hospital organization Higashi-Ohmi General Medical Center, Higashi-Ohmi, Japan.
¹⁰ Department of Neurology and Stroke Medicine, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
¹¹ Department of Neurology, Kobe City Medical Center General Hospital, Kobe, Japan.
¹² Department of Neurology, Anjo Kosei Hospital, Anjo, Japan.
¹³ Department of Neurology, Yokkaichi Municipal Hospital, Yokkaichi, Japan.
¹⁴ Department of Neurology, Hyogo Brain and Heart Center, Himeji, Japan.
¹⁵ Department of Neurology, Dokkyo Medical University, Tochigi, Japan.
¹⁶ Department of Neurology, Fukuoka University, Fukuoka, Japan.
¹⁷ Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
¹⁸ Artificial Intelligence Research Center, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
¹⁹ Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Tokyo, Japan.
²⁰ Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan.
²¹ Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
²² Graduate School of Frontier Sciences, University of Tokyo, Chiba, Japan.
²³ Computational Bio Big-Data Open Innovation Laboratory, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan.
²⁴ Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. naomat@yokohama-cu.ac.jp.
²⁵ Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan. sobueg@med.nagoya-u.ac.jp.
²⁶ Department of Neurology, and Brain and Mind Research Center, Nagoya University Graduate School of Medicine, Nagoya, Japan. sobueg@med.nagoya-u.ac.jp.
²⁷ Aichi Medical University, Nagakute, Aichi, Japan. sobueg@med.nagoya-u.ac.jp.

PMID: 31332381
DOI: 10.1038/s41588-019-0459-y

Abstract

Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease that is characterized by eosinophilic hyaline intranuclear inclusions in neuronal and somatic cells. The wide range of clinical manifestations in NIID makes ante-mortem diagnosis difficult^1-8, but skin biopsy enables its ante-mortem diagnosis^9-12. The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases. By linkage mapping of a large NIID family with several affected members (Family 1), we identified a 58.1 Mb linked region at 1p22.1-q21.3 with a maximum logarithm of the odds score of 4.21. By long-read sequencing, we identified a GGC repeat expansion in the 5' region of NOTCH2NLC (Notch 2 N-terminal like C) in all affected family members. Furthermore, we found similar expansions in 8 unrelated families with NIID and 40 sporadic NIID cases. We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals. This work shows that repeat expansion in human-specific NOTCH2NLC, a gene that evolved by segmental duplication, causes a human disease.

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Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease

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Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease

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