Novel ADAR2 variants in children with seizures, intellectual disability and motor delay have reduced RNA editing.
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216224%3A14740%2F25%3A00141765" target="_blank" >RIV/00216224:14740/25:00141765 - isvavai.cz</a>
Result on the web
<a href="https://rnajournal.cshlp.org/content/early/2025/06/06/rna.080600.125" target="_blank" >https://rnajournal.cshlp.org/content/early/2025/06/06/rna.080600.125</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1261/rna.080600.125" target="_blank" >10.1261/rna.080600.125</a>
Alternative languages
Result language
angličtina
Original language name
Novel ADAR2 variants in children with seizures, intellectual disability and motor delay have reduced RNA editing.
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10608 - Biochemistry and molecular biology
Result continuities
Project
<a href="/en/project/GX21-27329X" target="_blank" >GX21-27329X: ADAR RNA editing; how immune systems and brains breach The Central Dogma</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2025
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
RNA
ISSN
1355-8382
e-ISSN
1469-9001
Volume of the periodical
31
Issue of the periodical within the volume
9
Country of publishing house
US - UNITED STATES
Number of pages
18
Pages from-to
1287-1304
UT code for WoS article
001551446400001
EID of the result in the Scopus database
2-s2.0-105013808793