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

Year: 2020

Type: article

Abstract: 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.

Source: Journal of Medical Genetics

DOI: 10.1136/jmedgenet-2020-107048

Authors: Reza Maroofian, Jiří Sedmík, Neda Mazaheri, Marcello Scala, Maha S Zaki, Liam P Keegan, Reza Azizimalamiri, Mahmoud Issa, Gholamreza Shariati, Alireza Sedaghat, Christian Beetz, Peter Bauer, Hamid Galehdari, Mary A O’Connell, Henry Houlden

Institutions: UCL Queen Square Institute of Neurology, University College London, Central European Institute of Technology – Masaryk University, Shahid Chamran University of Ahvaz, University of Genoa, National Research Centre, Ahvaz Jundishapur University of Medical Sciences, Centogene (Germany)

Language: English

Topic: RNA regulation and disease

Subfield: Molecular Biology

Field: Biochemistry, Genetics and Molecular Biology

Domain: Life Sciences

SDG: Good health and well-being

Open Access status: hybrid

Funders: Muscular Dystrophy Association, Wellcome Trust, Muscular Dystrophy UK, Multiple System Atrophy Trust, Brain Research UK, National Institute for Health and Care Research, Ataxia UK, University College London, Rosetrees Trust, Great Ormond Street Hospital Charity, Ministerstvo Školství, Mládeže a Tělovýchovy, Grantová Agentura České Republiky, Central European Institute of Technology, Muscular Dystrophy UK, Medical Research Council

OpenAlex ID: W3044579751