Biallelic variants in ADARB1, encoding a dsRNA-specific
adenosine deaminase, cause a severe developmental and epileptic
encephalopathy

J 2021

Biallelic variants in ADARB1, encoding a dsRNA-specific adenosine deaminase, cause a severe developmental and epileptic encephalopathy

MAROOFIAN, Reza, Jiří SEDMÍK, Neda MAZAHERI, Marcello SCALA, Maha S. ZAKI et. al.

Základní údaje

Originální název

Biallelic variants in ADARB1, encoding a dsRNA-specific adenosine deaminase, cause a severe developmental and epileptic encephalopathy

Autoři

MAROOFIAN, Reza, Jiří SEDMÍK (203 Česká republika, domácí), Neda MAZAHERI, Marcello SCALA, Maha S. ZAKI, Liam KEEGAN (372 Irsko, domácí), Reza AZIZIMALAMIRI, Mahmoud ISSA, Gholamreza SHARIATI, Alireza SEDAGHAT, Christian BEETZ, Peter BAUER, Hamid GALEHDARI, Mary Anne O'CONNELL (372 Irsko, garant, domácí) a Henry HOULDEN

Vydání

Journal of Medical Genetics, London (UK), BMJ Publishing Group, 2021, 0022-2593

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10608 Biochemistry and molecular biology

Stát vydavatele

Velká Británie a Severní Irsko

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 5.941

Kód RIV

RIV/00216224:14740/21:00118751

Organizační jednotka

Středoevropský technologický institut

DOI

http://dx.doi.org/10.1136/jmedgenet-2020-107048

UT WoS

000680409100007

Klíčová slova anglicky

epilepsymutationmissenseDNAsequence analysisnervous system diseases

Štítky

CF CELLIM, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 9. 10. 2024 13:00, Mgr. Adéla Pešková

Anotace

V originále

Background: Adenosine-to-inosine RNA editing is a co-transcriptional/post-transcriptional modification of double-stranded RNA, catalysed by one of two active adenosine deaminases acting on RNA (ADARs), ADAR1 and ADAR2. ADARB1 encodes the enzyme ADAR2 that is highly expressed in the brain and essential to modulate the function of glutamate and serotonin receptors. Impaired ADAR2 editing causes early onset progressive epilepsy and premature death in mice. In humans, ADAR2 dysfunction has been very recently linked to a neurodevelopmental disorder with microcephaly and epilepsy in four unrelated subjects. Methods: We studied three children from two consanguineous families with severe developmental and epileptic encephalopathy (DEE) through detailed physical and instrumental examinations. Exome sequencing (ES) was used to identify ADARB1 mutations as the underlying genetic cause and in vitro assays with transiently transfected cells were performed to ascertain the impact on ADAR2 enzymatic activity and splicing. Results: All patients showed global developmental delay, intractable early infantile-onset seizures, microcephaly, severe-to-profound intellectual disability, axial hypotonia and progressive appendicular spasticity. ES revealed the novel missense c.1889G>A, p.(Arg630Gln) and deletion c.1245_1247+1 del, p.(Leu415PhefsTer14) variants in ADARB1 (NM_015833.4). The p.(Leu415PhefsTer14) variant leads to incorrect splicing resulting in frameshift with a premature stop codon and loss of enzyme function. In vitro RNA editing assays showed that the p.(Arg630Gln) variant resulted in a severe impairment of ADAR2 enzymatic activity. Conclusion: In conclusion, these data support the pathogenic role of biallelic ADARB1 variants as the cause of a distinctive form of DEE, reinforcing the importance of RNA editing in brain function and development.

Návaznosti

GA20-11101S, projekt VaV

Název: Objasnění úlohy RNA-editačního enzymu ADAR1 v nových biologických drahách a určení jeho postranslační regulace.

Investor: Grantová agentura ČR, Elucidating the role of the RNA editing enzyme ADAR1 in novel biological pathways and determine its posttranslational regulation.

90062, velká výzkumná infrastruktura

Název: Czech-BioImaging

Citovat

MAROOFIAN, Reza, Jiří SEDMÍK, Neda MAZAHERI, Marcello SCALA, Maha S. ZAKI, Liam KEEGAN, Reza AZIZIMALAMIRI, Mahmoud ISSA, Gholamreza SHARIATI, Alireza SEDAGHAT, Christian BEETZ, Peter BAUER, Hamid GALEHDARI, Mary Anne O'CONNELL a Henry HOULDEN. Biallelic variants in ADARB1, encoding a dsRNA-specific adenosine deaminase, cause a severe developmental and epileptic encephalopathy. Journal of Medical Genetics. London (UK): BMJ Publishing Group, 2021, roč. 58, č. 7, s. 495-504. ISSN 0022-2593. Dostupné z: https://dx.doi.org/10.1136/jmedgenet-2020-107048.

@article{1673938,
   author = {Maroofian, Reza and Sedmík, Jiří and Mazaheri, Neda and Scala, Marcello and Zaki, Maha S. and Keegan, Liam and Azizimalamiri, Reza and Issa, Mahmoud and Shariati, Gholamreza and Sedaghat, Alireza and Beetz, Christian and Bauer, Peter and Galehdari, Hamid and O'Connell, Mary Anne and Houlden, Henry},
   article_location = {London (UK)},
   article_number = {7},
   doi = {http://dx.doi.org/10.1136/jmedgenet-2020-107048},
   keywords = {epilepsymutationmissenseDNAsequence analysisnervous system diseases},
   language = {eng},
   issn = {0022-2593},
   journal = {Journal of Medical Genetics},
   title = {Biallelic variants in ADARB1, encoding a dsRNA-specific adenosine deaminase, cause a severe developmental and epileptic encephalopathy},
   url = {https://jmg.bmj.com/content/58/7/495},
   volume = {58},
   year = {2021}
}

TY  - JOUR
ID  - 1673938
AU  - Maroofian, Reza - Sedmík, Jiří - Mazaheri, Neda - Scala, Marcello - Zaki, Maha S. - Keegan, Liam - Azizimalamiri, Reza - Issa, Mahmoud - Shariati, Gholamreza - Sedaghat, Alireza - Beetz, Christian - Bauer, Peter - Galehdari, Hamid - O'Connell, Mary Anne - Houlden, Henry
PY  - 2021
TI  - Biallelic variants in ADARB1, encoding a dsRNA-specific adenosine deaminase, cause a severe developmental and epileptic encephalopathy
JF  - Journal of Medical Genetics
VL  - 58
IS  - 7
SP  - 495-504
EP  - 495-504
PB  - BMJ Publishing Group
SN  - 00222593
KW  - epilepsymutationmissenseDNAsequence analysisnervous system diseases
UR  - https://jmg.bmj.com/content/58/7/495
N2  - Background: Adenosine-to-inosine RNA editing is a co-transcriptional/post-transcriptional modification of double-stranded RNA, catalysed by one of two active adenosine deaminases acting on RNA (ADARs), ADAR1 and ADAR2. ADARB1 encodes the enzyme ADAR2 that is highly expressed in the brain and essential to modulate the function of glutamate and serotonin receptors. Impaired ADAR2 editing causes early onset progressive epilepsy and premature death in mice. In humans, ADAR2 dysfunction has been very recently linked to a neurodevelopmental disorder with microcephaly and epilepsy in four unrelated subjects. Methods: We studied three children from two consanguineous families with severe developmental and epileptic encephalopathy (DEE) through detailed physical and instrumental examinations. Exome sequencing (ES) was used to identify ADARB1 mutations as the underlying genetic cause and in vitro assays with transiently transfected cells were performed to ascertain the impact on ADAR2 enzymatic activity and splicing. Results: All patients showed global developmental delay, intractable early infantile-onset seizures, microcephaly, severe-to-profound intellectual disability, axial hypotonia and progressive appendicular spasticity. ES revealed the novel missense c.1889G>A, p.(Arg630Gln) and deletion c.1245_1247+1 del, p.(Leu415PhefsTer14) variants in ADARB1 (NM_015833.4). The p.(Leu415PhefsTer14) variant leads to incorrect splicing resulting in frameshift with a premature stop codon and loss of enzyme function. In vitro RNA editing assays showed that the p.(Arg630Gln) variant resulted in a severe impairment of ADAR2 enzymatic activity. Conclusion: In conclusion, these data support the pathogenic role of biallelic ADARB1 variants as the cause of a distinctive form of DEE, reinforcing the importance of RNA editing in brain function and development.
ER  -

MAROOFIAN, Reza, Jiří SEDMÍK, Neda MAZAHERI, Marcello SCALA, Maha S. ZAKI, Liam KEEGAN, Reza AZIZIMALAMIRI, Mahmoud ISSA, Gholamreza SHARIATI, Alireza SEDAGHAT, Christian BEETZ, Peter BAUER, Hamid GALEHDARI, Mary Anne O'CONNELL a Henry HOULDEN. Biallelic variants in ADARB1, encoding a dsRNA-specific adenosine deaminase, cause a severe developmental and epileptic encephalopathy. \textit{Journal of Medical Genetics}. London (UK): BMJ Publishing Group, 2021, roč.~58, č.~7, s.~495-504. ISSN~0022-2593. Dostupné z: https://dx.doi.org/10.1136/jmedgenet-2020-107048.

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