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

J 2025

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

DU, Qiupei; Anna CHERIAN; Raymond J LOUIE; Giulia BARCIA; Natasha RUDY et al.

Základní údaje

Originální název

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

Autoři

DU, Qiupei; Anna CHERIAN ; Raymond J LOUIE; Giulia BARCIA; Natasha RUDY; Rima NABBOUT; Eugenie SARDA; Maelle CHARPIE; Wesley G PATTERSON; Liam KEEGAN a Mary Anne O'CONNELL

Vydání

RNA, Cold Spring Harbor Laboratory Press, 2025, 1355-8382

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 5.000 v roce 2024

Označené pro přenos do RIV

Ano

Organizační jednotka

Středoevropský technologický institut

Klíčová slova anglicky

ADAR2; ADARB1; RNA editing; seizures

Štítky

143160, CF CELLIM, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 7. 3. 2026 19:47, Mgr. Eva Dubská

Anotace

V originále

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.

Návaznosti

GX21-27329X, projekt VaV

Název: ADAR-dependentní RNA editace; Jak imunitní systém a mozek porušují Centrální Dogma.

Investor: Grantová agentura ČR, ADAR RNA editing, how immune systems and brains breach The Central Dogma

90250, velká výzkumná infrastruktura

Název: Czech-BioImaging III

Citovat

DU, Qiupei; Anna CHERIAN; Raymond J LOUIE; Giulia BARCIA; Natasha RUDY; Rima NABBOUT; Eugenie SARDA; Maelle CHARPIE; Wesley G PATTERSON; Liam KEEGAN a Mary Anne O'CONNELL. Novel ADAR2 variants in children with seizures, intellectual disability and motor delay have reduced RNA editing. RNA. Cold Spring Harbor Laboratory Press, 2025, roč. 31, č. 9, s. 1287-1304. ISSN 1355-8382. Dostupné z: https://doi.org/10.1261/rna.080600.125.

@article{2511951,
   author = {Du, Qiupei and Cherian, Anna and Louie, Raymond J and Barcia, Giulia and Rudy, Natasha and Nabbout, Rima and Sarda, Eugenie and Charpie, Maelle and Patterson, Wesley G and Keegan, Liam and O'Connell, Mary Anne},
   article_number = {9},
   doi = {https://doi.org/10.1261/rna.080600.125},
   keywords = {ADAR2; ADARB1; RNA editing; seizures},
   language = {eng},
   issn = {1355-8382},
   journal = {RNA},
   title = {Novel ADAR2 variants in children with seizures, intellectual disability and motor delay have reduced RNA editing.},
   url = {https://rnajournal.cshlp.org/content/early/2025/06/06/rna.080600.125},
   volume = {31},
   year = {2025}
}

TY  - JOUR
ID  - 2511951
AU  - Du, Qiupei - Cherian, Anna - Louie, Raymond J - Barcia, Giulia - Rudy, Natasha - Nabbout, Rima - Sarda, Eugenie - Charpie, Maelle - Patterson, Wesley G - Keegan, Liam - O'Connell, Mary Anne
PY  - 2025
TI  - Novel ADAR2 variants in children with seizures, intellectual disability and motor delay have reduced RNA editing.
JF  - RNA
VL  - 31
IS  - 9
SP  - 1287-1304
EP  - 1287-1304
PB  - Cold Spring Harbor Laboratory Press
SN  - 13558382
KW  - ADAR2
KW  - ADARB1
KW  - RNA editing
KW  - seizures
UR  - https://rnajournal.cshlp.org/content/early/2025/06/06/rna.080600.125
N2  - 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.
ER  -

DU, Qiupei; Anna CHERIAN; Raymond J LOUIE; Giulia BARCIA; Natasha RUDY; Rima NABBOUT; Eugenie SARDA; Maelle CHARPIE; Wesley G PATTERSON; Liam KEEGAN a Mary Anne O'CONNELL. Novel ADAR2 variants in children with seizures, intellectual disability and motor delay have reduced RNA editing. \textit{RNA}. Cold Spring Harbor Laboratory Press, 2025, roč.~31, č.~9, s.~1287-1304. ISSN~1355-8382. Dostupné z: https://doi.org/10.1261/rna.080600.125.

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