Tan, TY;
Sedmik, J;
Fitzgerald, MP;
Halevy, RS;
Keegan, LP;
Helbig, I;
Basel-Salmon, L;
... O'Connell, MA; + view all
(2020)
Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures.
The American Journal of Human Genetics (AJHG)
, 106
(4)
pp. 467-483.
10.1016/j.ajhg.2020.02.015.
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Abstract
The RNA editing enzyme ADAR2 is essential for the recoding of brain transcripts. Impaired ADAR2 editing leads to early-onset epilepsy and premature death in a mouse model. Here, we report bi-allelic variants in ADARB1, the gene encoding ADAR2, in four unrelated individuals with microcephaly, intellectual disability, and epilepsy. In one individual, a homozygous variant in one of the double-stranded RNA-binding domains (dsRBDs) was identified. In the others, variants were situated in or around the deaminase domain. To evaluate the effects of these variants on ADAR2 enzymatic activity, we performed in vitro assays with recombinant proteins in HEK293T cells and ex vivo assays with fibroblasts derived from one of the individuals. We demonstrate that these ADAR2 variants lead to reduced editing activity on a known ADAR2 substrate. We also demonstrate that one variant leads to changes in splicing of ADARB1 transcript isoforms. These findings reinforce the importance of RNA editing in brain development and introduce ADARB1 as a genetic etiology in individuals with intellectual disability, microcephaly, and epilepsy.
| Type: | Article |
|---|---|
| Title: | Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.ajhg.2020.02.015 |
| Publisher version: | https://doi.org/10.1016/j.ajhg.2020.02.015 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Genetics & Heredity, MIGRATING PARTIAL SEIZURES, DYSCHROMATOSIS SYMMETRICA HEREDITARIA, RNA RECOGNITION, BINDING DOMAINS, MICE DEFICIENT, MESSENGER-RNA, INFANCY, GENE, MUTATIONS, ADENOSINE |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10107754 |
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