Novel ADAR2 variants in children with seizures, intellectual disability and motor delay have reduced RNA editing.
| Autoři | |
|---|---|
| Rok publikování | 2025 |
| Druh | Článek v odborném periodiku |
| Časopis / Zdroj | RNA |
| Fakulta / Pracoviště MU | |
| Citace | |
| www | https://rnajournal.cshlp.org/content/early/2025/06/06/rna.080600.125 |
| Doi | https://doi.org/10.1261/rna.080600.125 |
| Klíčová slova | ADAR2; ADARB1; RNA editing; seizures |
| Popis | The ADARB1 gene encodes the ADAR2 RNA editing enzyme, which edits the GRIA2 transcript Q/R editing site with almost 100% efficiency in the nervous system. The edited GRIA2R transcript encodes the GLUA2 R subunit isoform of tetrameric AMPA receptors, which is essential to prevent seizures associated with aberrantly elevated AMPA receptor cation permeability. Rare biallelic variants in ADARB1 cause severe infant and childhood seizures and developmental delays in seven cases we previously described. Here, we report two new homozygous ADARB1 variants and study ADAR2 variant editing activities at the GRIA2 Q/R site and other editing sites in cell cultures. One new variant in the second dsRNA binding domain (dsRBD II) retains up to 60% editing activity, whereas another, in the deaminase domain, eliminates RNA editing activity. Reduced GRIA2 Q/R site editing increases AMPA receptor permeability by upregulating the expression of the GLUA2 Q isoform and reducing overall GLUA2 subunit levels, resulting in AMPA receptors that lack GLUA2 and are calcium-permeable. Since failure to edit the GRIA2 Q/R site leads to failure of intron 11 splicing, we also examined the effects of ADAR2 variants on the splicing of a mouse Gria2-based reporter and concluded that ADAR2 variants affect splicing only through their effects on RNA editing activity. To expand the number of variants in ADARB1, some variants reported in ClinVar have also been analysed by in silico methods to predict which are likely to be most deleterious and associated with seizures in patients. |
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