ARX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

抄録

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.