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

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Authors	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
Year of publication	2021
Type	Article in Periodical
Magazine / Source	Journal of Medical Genetics
MU Faculty or unit	Central European Institute of Technology
Citation
Web	https://jmg.bmj.com/content/58/7/495
Doi	http://dx.doi.org/10.1136/jmedgenet-2020-107048
Keywords	epilepsymutationmissenseDNAsequence analysisnervous system diseases
Description	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.
Related projects:	Elucidating the role of the RNA editing enzyme ADAR1 in novel biological pathways and determine its posttranslational regulation.