Informace o publikaci

Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures

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TAN Tiong Yang SEDMÍK Jiří FITZGERALD Mark P. SUKENIK HALEVY Rivka KEEGAN Liam HELBIG Ingo BASEL-SALMON Lina COHEN Lior STRAUSSBERG Rachel CHUNG Wendy K. HELAL Mayada MAROOFIAN Reza HOULDEN Henry JUUSOLA Jane SADEDIN Simon PAIS Lynn HOWELL Katherine B. WHITE Susan M. CHRISTODOULOU John O'CONNELL Mary Anne

Rok publikování 2020
Druh Článek v odborném periodiku
Časopis / Zdroj The American Journal of Human Genetics
Fakulta / Pracoviště MU

Středoevropský technologický institut

Citace
www https://www.cell.com/ajhg/pdf/S0002-9297(20)30057-4.pdf
Doi http://dx.doi.org/10.1016/j.ajhg.2020.02.015
Klíčová slova ADAR2; microcephaly; migrating focal seizures; epilepsy; intellectual disability; RNA editing
Popis 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.
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