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Biallelic variants in ADARB1, encoding a dsRNA-specific adenosine deaminase, cause a severe developmental and epileptic encephalopathy
R. Maroofian, J. Sedmík, N. Mazaheri, M. Scala, MS. Zaki, LP. Keegan, R. Azizimalamiri, M. Issa, G. Shariati, A. Sedaghat, C. Beetz, P. Bauer, H. Galehdari, MA. O'Connell, H. Houlden
Language English Country Great Britain
Document type Case Reports, Journal Article, Research Support, Non-U.S. Gov't
Grant support
Wellcome Trust - United Kingdom
MR/S01165X/1
Medical Research Council - United Kingdom
MR/S005021/1
Medical Research Council - United Kingdom
WT093205MA
Wellcome Trust - United Kingdom
WT104033AIA
Wellcome Trust - United Kingdom
NLK
ProQuest Central
from 1994-01-01 to 6 months ago
Health & Medicine (ProQuest)
from 1994-01-01 to 6 months ago
- MeSH
- Adenosine Deaminase genetics metabolism MeSH
- Alleles MeSH
- Child MeSH
- RNA, Double-Stranded metabolism MeSH
- RNA Editing MeSH
- Epilepsy enzymology genetics MeSH
- HEK293 Cells MeSH
- Humans MeSH
- Mutation MeSH
- Brain Diseases enzymology genetics metabolism MeSH
- Neurodevelopmental Disorders enzymology genetics MeSH
- Consanguinity MeSH
- Child, Preschool MeSH
- RNA-Binding Proteins genetics metabolism MeSH
- Pedigree MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Case Reports MeSH
- Research Support, Non-U.S. Gov't MeSH
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.
CEITEC Masaryk University Kamenice 735 5 A35 Brno 62500 Czech Republic
Department of Genetics Faculty of Science Shahid Chamran University of Ahvaz Ahvaz Iran
Department of Neuromuscular Disorders UCL Queen Square Institute of Neurology London WC1N 3BG UK
References provided by Crossref.org
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