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

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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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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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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Kuroda, Y., Naruto, T., Tsuyusaki, Y. et al. Role of TOE1 variants at the nuclear localization motif in pontocerebellar hypoplasia 7. J Hum Genet 69, 349–355 (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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