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C-terminal truncations in IQSEC2: implications for synaptic localization, guanine nucleotide exchange factor activity, and neurological manifestations

Journal of Human Genetics volume 69, pages 119–123 (2024)Cite this article

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Abstract

IQSEC2 gene on chromosome Xq11.22 encodes a member of guanine nucleotide exchange factor (GEF) protein that is implicated in the activation of ADP-ribosylation factors (Arfs) at the postsynaptic density (PSD), and plays a crucial role in synaptic transmission and dendritic spine formation. Alterations in IQSEC2 have been linked to X-linked intellectual developmental disorders including epilepsy and behavioral abnormalities. Of interest, truncating variants at the C-terminus of IQSEC2 can cause severe phenotypes, akin to truncating variants located in other regions. Here, we present a 5-year-old boy with severe intellectual disability and progressive epilepsy. The individual carried a nonsense variant p.Q1227* in the last exon of the IQSEC2 gene that was supposed to escape nonsense-mediated mRNA decay, thereby leading to a translation of C-terminus truncated IQSEC2 protein with residual activity. The functional analyses showed that the GEF activity of IQSEC2 Q1227* was compromised, and that the IQSEC2 Q1227* lacked preferential synaptic localization due to the absence of functional domains for binding to scaffolding proteins in the PSD. The impaired GEF activity and disrupted synaptic localization of the mutant IQSEC2 protein could impact dendritic and spine development in neurons, potentially explaining the patient’s severe neurological manifestations. Our findings indicate that C-terminal truncations in IQSEC2, previously not well-characterized, may have significant pathogenic implications.

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Acknowledgements

The authors are grateful to the patient and parents for their cooperation. This work was supported in part by JSPS KAKENHI (Grant numbers: 19H03628, 21K19751, 22H03048, and 23K06322).

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Authors and Affiliations

  1. Department of Medical Genetics, NHO Tokyo Medical Center, Tokyo, 152-8902, Japan

    Moeko Nakashima & Kazuki Yamazawa

  2. Department of Anatomy, Kitasato University School of Medicine, Sagamihara, 252-0374, Japan

    Tomoko Shiroshima, Masahiro Fukaya, Takeyuki Sugawara & Hiroyuki Sakagami

Authors
  1. Moeko Nakashima
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  2. Tomoko Shiroshima
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  3. Masahiro Fukaya
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  4. Takeyuki Sugawara
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  5. Hiroyuki Sakagami
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  6. Kazuki Yamazawa
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Correspondence to Hiroyuki Sakagami or Kazuki Yamazawa.

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Nakashima, M., Shiroshima, T., Fukaya, M. et al. C-terminal truncations in IQSEC2: implications for synaptic localization, guanine nucleotide exchange factor activity, and neurological manifestations. J Hum Genet 69, 119–123 (2024). https://doi.org/10.1038/s10038-023-01210-9

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