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<p>AKT3, a key component of the PI3K-AKT-MTOR pathway, is highly expressed in the brain, and its activating variants cause megalencephaly and cortical malformations. In this study, we functionally verified a novel missense <i>AKT3</i> variant (p.Q78R) identified in a patient with extreme megalencephaly and intractable epilepsy. We transiently transfected HEK-293T cells with the AKT<sup>WT</sup> or AKT3<sup>Q78R</sup> and observed a significant increase of phospho-S6, a marker of mTOR complex 1 (mTORC1) activity, in AKT3<sup>Q78R</sup> transfected cells. Furthermore, considering its application in epilepsy treatment research, we identified a small interfering RNA (siRNA) capable of reducing the mRNA levels of <i>AKT</i><sup><i>Q78R</i></sup> without affecting the expression levels of <i>AKT3</i><sup><i>WT</i></sup>. Finally, the siRNA we identified specifically suppressed the AKT3<sup>Q78R</sup>-mediated mTORC1 activity, suggesting that this allele-specific siRNA approach holds promise for ameliorating the pathological condition.</p>

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Functional verification and allele-specific silencing of a novel AKT3 variant that causes megalencephaly, polymicrogyria and intractable epilepsy

  • 期刊论文

  • 发表日期：

    2025年3月8日

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  • Yosuke Miyamoto,
  • Takenori Tozawa,
  • Eisuke Ichise,
  • Tatsuji Hasegawa,
  • Takahiro Fujimoto,
  • Kyoko Itoh,
  • Masafumi Morimoto,
  • Tomoko Iehara,
  • Tomohiro Chiyonobu

摘要

AKT3, a key component of the PI3K-AKT-MTOR pathway, is highly expressed in the brain, and its activating variants cause megalencephaly and cortical malformations. In this study, we functionally verified a novel missense AKT3 variant (p.Q78R) identified in a patient with extreme megalencephaly and intractable epilepsy. We transiently transfected HEK-293T cells with the AKTWT or AKT3Q78R and observed a significant increase of phospho-S6, a marker of mTOR complex 1 (mTORC1) activity, in AKT3Q78R transfected cells. Furthermore, considering its application in epilepsy treatment research, we identified a small interfering RNA (siRNA) capable of reducing the mRNA levels of AKTQ78R without affecting the expression levels of AKT3WT. Finally, the siRNA we identified specifically suppressed the AKT3Q78R-mediated mTORC1 activity, suggesting that this allele-specific siRNA approach holds promise for ameliorating the pathological condition.