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An intronic GNAO1 variant leading to in-frame insertion cause movement disorder controlled by deep brain stimulation

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Abstract

GNAO1 variants are associated with a wide range of neurodevelopmental disorders including epileptic encephalopathies and movement disorders. It has been reported that some GNAO1 variants are associated with movement disorders, and the 207–246 amino acid region was proposed as a mutational hotspot. Here, we report an intronic variant (NM_020988.3:c.724-8G>A) in GNAO1 in a Japanese girl who showed mild developmental delay and movement disorders including dystonia and myoclonus. Her movement disorders were improved by deep brain stimulation treatment as previously reported. This variant has been recurrently reported in four patients and was transmitted from her mother who possessed the variant as low-prevalent mosaicism. Using RNA extracted from lymphoblastoid cells derived from the patient, we demonstrated that the variant caused abnormal splicing of in-frame 6-bp intronic retention, leading to 2 amino acid insertion (p.Thr241_Asn242insProGln). Immunoblotting and immunostaining using WT and mutant GNAO1 vectors showed no significant differences in protein expression levels, but the cellular localization pattern of this mutant was partially shifted to the cytoplasm whereas WT was exclusively localized in the cellular membrane. Our report first clarified abnormal splicing and resulting mutant protein caused by the c.724-8G>A variant.

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Acknowledgements

We would like to thank the patient’s family for participating in this work. We also thank K. Shibazaki, M. Tsujimura, and A. Kitamoto for their technical assistance. This work was supported by the Grants-in-Aid for Scientific Research (B) (JP20H03641), HUSM Grant-in-Aid from Hamamatsu University School of Medicine, and the Takeda Science Foundation.

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Authors and Affiliations

  1. Department of Biochemistry, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan

    Sachiko Miyamoto, Mitsuko Nakashima & Hirotomo Saitsu

  2. Department of Pediatrics, Sapporo Medical University School of Medicine, Sapporo, Japan

    Shinobu Fukumura

  3. Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan

    Satoko Kumada

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  1. Sachiko Miyamoto
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  2. Mitsuko Nakashima
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  4. Satoko Kumada
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  5. Hirotomo Saitsu
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Contributions

SM, MN, and HS contributed data analysis. SM performed RT-PCR, cell culture, transfection, and immunoblotting analysis; SF and SK evaluated the patient and provided samples. HS conceived and designed the study. All authors contributed to writing the manuscript.

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Correspondence to Hirotomo Saitsu.

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The authors declare no competing interests.

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Miyamoto, S., Nakashima, M., Fukumura, S. et al. An intronic GNAO1 variant leading to in-frame insertion cause movement disorder controlled by deep brain stimulation. Neurogenetics 23, 129–135 (2022). https://doi.org/10.1007/s10048-022-00686-5

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  • DOI: https://doi.org/10.1007/s10048-022-00686-5

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