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Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease

Nature Genetics volume 51, pages 1222–1232 (2019)Cite this article

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Abstract

Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1, we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively. These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases.

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Fig. 1: Brain MRI of patients with FXTAS, NIID, OPML and OPDM.
Fig. 2: Direct identification of repeat expansion mutations by analysis of short reads of whole-genome sequence data.
Fig. 3: Identification of CGG repeat expansion mutations in NBPF19 in NIID.
Fig. 4: Characterization of CGG repeat expansion mutations in the 5′ UTR of NBPF19 in patients with NIID.
Fig. 5: Identification of CGG repeat expansions in LOC642361/NUTM2B-AS1 in a family with OPML.
Fig. 6: Identification of CGG repeat expansions in LRP12 in families with OPDM.

Data availability

The genotyping microarray data and sequence data obtained by massively parallel sequencing analysis, including whole-genome sequencing and transcriptome analyses, are available on request from the corresponding author. Since whole-genome sequence data are protected by the Personal Information Protection Law, these data are available under regulation by the institutional review board.

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Acknowledgements

We thank the patients and family members for participating in the study. We also thank the neurologists, pathologists and radiologists of the patients for collecting and providing clinical information, K. J. L. Porto for proofreading, and K. Hirayama, M. Takeyama, Z. Wu and K. Wakabayashi for technical support. This work was supported in part by KAKENHI (Grants-in-Aid for Scientific Research on Innovative Areas (numbers 22129001 and 22129002) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Grants-in-Aid (H23-Jitsuyoka (Nanbyo)-Ippan-004 and H26-Jitsuyoka (Nanbyo)-Ippan-080) from the Ministry of Health, Labour and Welfare, Japan, and grants (numbers 15ek0108065h0002, 16kk0205001h0001, 17kk0205001h0002 and 17ek0109279h0001) from the Japan Agency for Medical Research and Development; all to S.T.). This work was also supported by KAKENHI (Grants-in-Aid for Young Scientists (numbers 15K20941 and 17H05085) from the Japan Society for the Promotion of Science; to H.I) and the Advanced Genome Research and Bioinformatics Study to Facilitate Medical Innovation (GRIFIN) from the Japan Agency for Medical Research and Development (to S. Morishita).

Author information

Author notes

  1. Koichiro Doi

    Present address: School of Bioscience and Biotechnology, Tokyo University of Technology, Tokyo, Japan

  2. Makiko Taira

    Present address: Department of Integrative Genomics, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan

  3. Hisatomo Kowa

    Present address: Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan

  4. Yasuo Terao

    Present address: Department of Cell Physiology, Kyorin University School of Medicine, Tokyo, Japan

Authors and Affiliations

  1. Department of Neurology, The University of Tokyo Hospital, Tokyo, Japan

    Hiroyuki Ishiura, Shota Shibata, M. Asem Almansour, Junko Kanda Kikuchi, Makiko Taira, Jun Mitsui, Yuji Takahashi, Yaeko Ichikawa, Tatsuo Mano, Atsushi Iwata, Miho Kawabe Matsukawa, Takashi Matsukawa, Masaki Tanaka, Yuichiro Shirota, Ryo Ohtomo, Hisatomo Kowa, Hidetoshi Date, Aki Mitsue, Akihiko Mitsutake, Mizuho Kawai, Takuya Sasaki, Yusuke Sugiyama, Masashi Hamada, Gaku Ohtomo, Yasuo Terao, Jun Shinmi, Jun Shimizu, Jun Goto, Tatsushi Toda & Shoji Tsuji

  2. Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Chiba, Japan

    Jun Yoshimura, Yuta Suzuki, Wei Qu, Koichiro Doi & Shinichi Morishita

  3. Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Jun Mitsui, Takashi Matsukawa & Shoji Tsuji

  4. Department of Neurology, National Center of Neurology and Psychiatry, Tokyo, Japan

    Yuji Takahashi & Hidetoshi Date

  5. Department of Neurology, Kyorin University, Tokyo, Japan

    Yaeko Ichikawa

  6. Department of Neurology, Maebashi Red Cross Hospital, Maebashi, Japan

    Yasuo Harigaya

  7. Institute of Medical Genomics, International University of Health and Welfare, Chiba, Japan

    Masaki Tanaka & Shoji Tsuji

  8. Department of Neurology and Neuropathology (the Brain Bank for Aging Research), Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan

    Hiroyuki Hatsuta, Satoru Morimoto & Shigeo Murayama

  9. Department of Neurology, Osaka City University Graduate School of Medicine, Osaka, Japan

    Hiroyuki Hatsuta & Akitoshi Takeda

  10. Department of Neurology, Tokyo Teishin Hospital, Tokyo, Japan

    Yasushi Shiio

  11. Department of Pathology and Laboratory Medicine, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan

    Yuko Saito

  12. Department of Neurology, Saitama Medical University, Saitama, Japan

    Yoshihiko Nakazato

  13. Department of Neurology, Jichi Medical University, Saitama Medical Center, Saitama, Japan

    Yoshio Sakiyama

  14. Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Yumi Umeda-Kameyama

  15. Department of Neurology, National Hospital Organization Higashisaitama Hospital, Saitama, Japan

    Katsuhisa Ogata

  16. Department of Neurology, Ibaraki Prefectural University of Health Sciences, Ami, Japan

    Yutaka Kohno

  17. Division of Neurology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

    Shen-Yang Lim & Ai Huey Tan

  18. Department of Neurology, International University of Health and Welfare Mita Hospital, Tokyo, Japan

    Jun Goto

  19. Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo, Japan

    Ichizo Nishino

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  1. Hiroyuki Ishiura
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Contributions

H.I. and S.T. designed the research. H.I., S.S., M.A.A., J.K., M.Taira, J.M., Y.Takahashi, Y.I., T.Matsukawa, M.Tanaka, H.D., J.G., T.T. and S.T. performed the experiments and/or analyzed the data. H.I., S.S., J.Y., Y.Suzuki., W.Q., K.D. and S.Morishita performed the computational analysis. H.I., S.S., J.K., M.Taira, J.M., Y.Takahashi, Y.I., T.Mano, A.I., Y.H., M.K.M., T.Matsukawa, M.Tanaka, Y.Shirota, R.O., H.K., A.Mitsue., H.H., S.Morimoto, S.Murayama, Y.Shiio, Y.Saito, A.Mitsutake, M.K., T.S., Y.Sugiyama, M.H., G.O., Y.Terao, Y.N., A.T., Y.Sakiyama, Y.U.-K., J.Shinmi, K.O., Y.K., S.-Y.L., A.H.T., J.Shimizu, J.G., I.N., T.T. and S.T. collected and analyzed the clinical data and/or provided patients’ samples. H.I. and S.T. wrote the manuscript, together with contributions from S.S. and S.Morishita. All authors contributed to and critically reviewed the manuscript.

Corresponding author

Correspondence to Shoji Tsuji.

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Ishiura, H., Shibata, S., Yoshimura, J. et al. Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease. Nat Genet 51, 1222–1232 (2019). https://doi.org/10.1038/s41588-019-0458-z

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