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Role of TOE1 variants at the nuclear localization motif in pontocerebellar hypoplasia 7

Journal of Human Genetics (2024)Cite this article

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Abstract

Biallelic TOE1 variants can cause pontocerebellar hypoplasia type 7 (PCH7), a condition characterized by pontocerebellar hypoplasia with genital abnormality. TOE1 is a 3’-exonuclese for 3’-end maturation in small nuclear RNA. TOE1 pathogenic variants have been reported at the DEDD catalytic domain and zinc finger motif. Here, we describe a PCH7 patient with novel compound heterozygous TOE1 variants and a detailed clinical course. The patient was a 3-year-old female and showed developmental delay without cerebellar ataxic behavior. Head MRI revealed delayed myelination without pontocerebellar hypoplasia at 9 months of age. Progressive pontocerebellar atrophy was prominent at follow-up MRI. Cerebral abnormalities are characteristic features of PCH7 before pontocerebellar atrophy is observed. One variant, p.Arg331*, was located at the nuclear localization motif (NLM) and partially escaped from nonsense-mediated decay. This variant affected nuclear localization in mutant expressing cells, thus, the TOE1 variant at NLM leads to TOE1 dysfunction associated with nuclear mis-localization.

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Data availability

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

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Acknowledgements

This study was supported by The Initiative on Rare and Undiagnosed Diseases (Grant number 23ek0109549) from the Japan Agency for Medical Research and Development, MHLW Health Labour Sciences Research Grant 23FC1052, and JSPS KAKENHI Grant Number 23K14966 (YK). We thank the patient and her family for their cooperation.

Funding

The Initiative on Rare and Undiagnosed Diseases (Grant number 23ek0109549) from the Japan Agency for Medical Research and Development MHLW Health Labour Sciences Research Grant 23FC1052 JSPS KAKENHI Grant Number 23K14966 (YK).

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Authors and Affiliations

  1. Division of Medical Genetics, Kanagawa Children’s Medical Center, Yokohama, Japan

    Yukiko Kuroda & Kenji Kurosawa

  2. Clinical Research Institute, Kanagawa Children’s Medical Center, Yokohama, Japan

    Takuya Naruto & Kenji Kurosawa

  3. Division of Neurology, Kanagawa Children’s Medical Center, Yokohama, Japan

    Yu Tsuyusaki

  4. Division of Radiology, Kanagawa Children’s Medical Center, Yokohama, Japan

    Ayumi Kato & Noriko Aida

  5. Department of Diagnostic Radiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Ayumi Kato

Authors
  1. Yukiko Kuroda
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  2. Takuya Naruto
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  3. Yu Tsuyusaki
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  4. Ayumi Kato
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  5. Noriko Aida
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  6. Kenji Kurosawa
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Contributions

Kenji Kurosawa designed the study. Takuya Naruto performed the bioinformatics experiments. Yukiko Kuroda and Takuya Naruto contributed to the genetics experiments. Yukiko Kuroda, Yu Tsuyusaki, Ayumi Kato, Noriko Aida recruited and evaluated the study subjects. Kenji Kurosawa supervised Yukiko Kuroda. Kenji Kurosawa supervised and evaluated data with Yukiko Kuroda. Yukiko Kuroda wrote the manuscript.

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Correspondence to Yukiko Kuroda or Kenji Kurosawa.

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The authors declare no competing interests.

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Kuroda, Y., Naruto, T., Tsuyusaki, Y. et al. Role of TOE1 variants at the nuclear localization motif in pontocerebellar hypoplasia 7. J Hum Genet (2024). https://doi.org/10.1038/s10038-024-01244-7

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  • DOI: https://doi.org/10.1038/s10038-024-01244-7

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