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@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 and 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, vol.~58, No~7, p.~495-504. ISSN~0022-2593. Available from: https://dx.doi.org/10.1136/jmedgenet-2020-107048.
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