Novel ADAR2 variants in children with seizures, intellectual disability and motor delay have reduced RNA editing.

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

Novel ADAR2 variants in children with seizures, intellectual disability and motor delay have reduced RNA editing.

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

Novel ADAR2 variants in children with seizures, intellectual disability and motor delay have reduced RNA editing.

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/GX21-27329X" target="_blank" >GX21-27329X: ADAR-dependentní RNA editace; Jak imunitní systém a mozek porušují Centrální Dogma.</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

RNA

ISSN

1355-8382

e-ISSN

1469-9001

Svazek periodika

31

Číslo periodika v rámci svazku

9

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

18

Strana od-do

1287-1304

Kód UT WoS článku

001551446400001

EID výsledku v databázi Scopus

2-s2.0-105013808793