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Hexanucleotide repeat expansion in SCA36 reduces the expression of genes involved in ribosome biosynthesis and protein translation

Journal of Human Genetics (2024)Cite this article

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Abstract

Hereditary spinocerebellar ataxia (SCA) is a group of clinically and genetically heterogeneous inherited disorders characterized by slowly progressive cerebellar ataxia. We ascertained a Japanese pedigree with autosomal dominant SCA comprising four family members, including two patients. We identified a GGCCTG repeat expansion of intron 1 in the NOP56 gene by Southern blotting, resulting in a molecular diagnosis of SCA36. RNA sequencing using peripheral blood revealed that the expression of genes involved in ribosomal organization and translation was decreased in patients carrying the GGCCTG repeat expansion. Genes involved in pathways associated with ribosomal organization and translation were enriched and differentially expressed in the patients. We propose a novel hypothesis that the GGCCTG repeat expansion contributes to the pathogenesis of SCA36 by causing a global disruption of translation resulting from ribosomal dysfunction.

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Acknowledgements

The authors thank all participants who provided their samples in this study. This work was supported in part by the Grants-in-Aid from MEXT; JP26460411, JP23K06853 for S.M. and the MEXT Cooperative Research Project Program, Medical Research Center Initiative for High Depth Omics, and CURE: JPMXP1323015486 for MIB, Kyushu University of the Medical Institute of Bioregulation, Kyushu University. We appreciate the technical assistance and discussion regarding Southern blotting from Yoshikazu Totsuka, Tomoko Saito, Makiko Nakamura, and Naoki Kumagai at the Institute of Immunology Co., Ltd. We also appreciate technical assistance from The Research Support Center, Research Center for Human Disease Modeling, and Kyushu University Graduate School of Medical Science.

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Authors and Affiliations

  1. Division of Genomics, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Takuya Morikawa, Shigeyoshi Hiruki, Yinrui Sun & Hiroki Shibata

  2. Department of Neurology and Geriatric Medicine, Ehime University Graduate School of Medicine, Shitsukawa, Toon, 791-0295, Japan

    Shiroh Miura

  3. Department of Radiology, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, 830-0011, Japan

    Yusuke Uchiyama

  4. Department of Food and Nutrition, Beppu University Junior College, 82, Kitaishigaki, Oita, 874-8501, Japan

    Ryuta Fujioka

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  1. Takuya Morikawa
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Contributions

T.M., S.M., and H.S. designed the experiments. T.M., S.M., S.H., Y.S., R.F., and H.S. prepared the samples and performed the experiments. S.M. and Y.U. collected data on clinical features. R.F., S.M., and H.S. supervised the project. T.M., S.M., and H.S. wrote the manuscript with contributions from all authors. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Hiroki Shibata.

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Informed consent was obtained from all the subjects involved in the study. This study was conducted in accordance with the Declaration of Helsinki. The Ethics Committees of Kurume University School of Medicine and Kyushu University Faculty of Medicine issued approvals (#173 and #607-00, respectively).

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The authors declare no competing interests.

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Morikawa, T., Miura, S., Uchiyama, Y. et al. Hexanucleotide repeat expansion in SCA36 reduces the expression of genes involved in ribosome biosynthesis and protein translation. J Hum Genet (2024). https://doi.org/10.1038/s10038-024-01260-7

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  • DOI: https://doi.org/10.1038/s10038-024-01260-7

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