Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures.
Adenosine Deaminase
/ genetics
Alleles
Alternative Splicing
/ genetics
Child
Child, Preschool
Genetic Predisposition to Disease
/ genetics
Genetic Variation
/ genetics
HEK293 Cells
Humans
Intellectual Disability
/ genetics
Male
Microcephaly
/ genetics
RNA Splicing
/ genetics
RNA-Binding Proteins
/ genetics
Seizures
/ genetics
ADAR2
RNA editing
epilepsy
intellectual disability
microcephaly
migrating focal seizures
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
02 04 2020
02 04 2020
Historique:
received:
12
11
2019
accepted:
26
02
2020
pubmed:
30
3
2020
medline:
12
5
2020
entrez:
30
3
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32220291
pii: S0002-9297(20)30057-4
doi: 10.1016/j.ajhg.2020.02.015
pmc: PMC7118584
pii:
doi:
Substances chimiques
RNA-Binding Proteins
0
ADARB1 protein, human
EC 3.5.4.4
Adenosine Deaminase
EC 3.5.4.4
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
467-483Subventions
Organisme : NHGRI NIH HHS
ID : UM1 HG008900
Pays : United States
Informations de copyright
Copyright © 2020 American Society of Human Genetics. All rights reserved.
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