GCG repeat expansion in <i>ARX</i> gene inhibits ARX protein translation through the ectopic formation of RNA G-quadruplex
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- Kawakubo Kosuke
- Department of Genomic Neurology, Institute of Molecular Embryology and Genetics(IMEG), Kumamoto University, Japan Graduate School of Pharmaceutical Sciences, Kumamoto University, Japan
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- Asamitu Sefan
- Department of Genomic Neurology, Institute of Molecular Embryology and Genetics(IMEG), Kumamoto University, Japan
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- Yabuki Yasushi
- Department of Genomic Neurology, Institute of Molecular Embryology and Genetics(IMEG), Kumamoto University, Japan Graduate School of Pharmaceutical Sciences, Kumamoto University, Japan
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- Shioda Norifumi
- Department of Genomic Neurology, Institute of Molecular Embryology and Genetics(IMEG), Kumamoto University, Japan Graduate School of Pharmaceutical Sciences, Kumamoto University, Japan
Bibliographic Information
- Other Title
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- <i>ARX</i>遺伝子GCGリピート伸長はRNAグアニン四重鎖を介してARXタンパク質の翻訳抑制を引き起こす
Abstract
<p>Aristaless-related homeobox (ARX) is a crucial gene involved in the development of interneurons in the fetal brain. The ARX gene mutations are a significant contributor to X-Linked intellectual disability (XLID) including epilepsy. We investigated that the pathological mechanism of ARX-associated XLID in the most frequent polyalanine expansion mutation [c.334ins(GCG)7], termed GCG17. Biophysical analyses in circular dichroism (CD) spectra and thioflavin T assay revealed that GCG17 formed a parallel RNA G-quadruplex (G4RNA) exhibiting the stereotypical potassium specificity in vitro, but a control GCG10 and GCG10+GCA7 repeat RNA did not. Consistent with the results, the GCG17 stably expressing cells decreased the polyalanine expression compared to that of GCG10 and GCG10+GCA7 cells without changing these mRNA levels. G4RNAs are secondary structures proposed to function as negative regulators of post-transcriptional mRNA translation. Further, a mouse model of ARX-associated XLID shows the decrease of ARX protein translation. Taken together, inhibition of ARX protein translation by GCG17-derived ectopic G4RNA formation may cause ARX-associated XLID.</p>
Journal
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- Proceedings for Annual Meeting of The Japanese Pharmacological Society
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Proceedings for Annual Meeting of The Japanese Pharmacological Society 94 (0), 2-O-B1-2-, 2021
Japanese Pharmacological Society
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Keywords
Details 詳細情報について
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- CRID
- 1390005966211638144
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- NII Article ID
- 130008001444
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- ISSN
- 24354953
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- Text Lang
- ja
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- Data Source
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- JaLC
- Crossref
- CiNii Articles
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- Abstract License Flag
- Disallowed