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.

中文翻译：

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与小头畸形，智力障碍和癫痫发作相关的双等位基因ADARB1变体。

RNA编辑酶ADAR2对于大脑转录物的编码至关重要。ADAR2编辑功能受损会导致小鼠模型中的早发型癫痫和过早死亡。在这里，我们报告了四个无关联的小头畸形，智力残疾和癫痫患者的ADARB1（编码ADAR2的基因）中的双等位基因变异。在一个个体中，鉴定了双链RNA结合结构域（dsRBD）之一中的纯合变体。在另一些中，变体位于脱氨酶结构域内或周围。为了评估这些变体对ADAR2酶活性的影响，我们使用HEK293T细胞中的重组蛋白进行了体外测定，并使用了衍生自其中一个个体的成纤维细胞进行了离体测定。我们证明，这些ADAR2变体导致已知ADAR2基板上的编辑活动减少。我们还证明了一种变体导致ADARB1转录亚型剪接的变化。这些发现加强了RNA编辑在大脑发育中的重要性，并将ADARB1作为遗传病因引入了智障，小头畸形和癫痫病患者。