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

Tan, Tiong Yang; Sedmik, Jiri; Fitzgerald, Mark P.; Halevy, Rivka Sukenik; Keegan, Liam P.; 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; White, Susan; Christodoulou, John; O’Connell, Mary A.

doi:10.1016/j.ajhg.2020.02.015

Cited by 34 publications

(39 citation statements)

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“…Similarly, heterozygous ADARB1 variants did not lead to epilepsy in the subjects of the above-mentioned study, whereas biallelic variants resulted in a severe encephalopathy. 10 In agreement with these observations, the loss-of-function observed/expected upper bound fraction is 0.4 and ADARB1 is predicted to be likely associated with a recessive rather than a dominant disorder by DOMINO. 19 The main molecular pathogenic mechanism underlying ADARB1-related encephalopathy is most likely represented by the ADAR2-mediated recoding of brain pre-mRNAs.…”

Section: Discussionsupporting

confidence: 70%

“…For the editing assay, HEK 293 T cells were co-transfected with two plasmids, the ADAR2 expression vector and the RNA editing substrate expression vector, and the RNA from transfected cells was isolated as previously described. 10 RT-PCR was performed with RevertAid RT Kit (Thermo Fisher) according to the manufacturer's instructions with 2.5 µM of oligo(dT) 18 used as a primer. PCR products encompassing the pri-mir-376a2 editing site +4 or the Gria2 Q/R editing site were subjected to Sanger sequencing, and the peak heights at the editing sites were measured from the sequencing chromatograms.…”

Section: Rna Editing Assay and Splicing Assaymentioning

confidence: 99%

“…For the splicing assay, the transfection of SH-SY5Y and HeLa cells with the splicing reporter plasmid, the RNA isolation and the RT-PCR were all performed as described previously. 10 The primers used for the splicing assay PCR were: Spl1 (Fw): 5'-TTCTCACTTGGTGGAAGC-3'; Spl2 (Rv): 5'-CCAGTTGGTAGAGAGAGC-3'.…”

Section: Rna Editing Assay and Splicing Assaymentioning

confidence: 99%

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Biallelic variants in ADARB1, encoding a dsRNA-specific adenosine deaminase, cause a severe developmental and epileptic encephalopathy

et al. 2020

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BackgroundAdenosine-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.MethodsWe 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.ResultsAll 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.ConclusionIn 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.

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Section: Discussionsupporting

confidence: 70%

Section: Rna Editing Assay and Splicing Assaymentioning

confidence: 99%

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Biallelic variants in ADARB1, encoding a dsRNA-specific adenosine deaminase, cause a severe developmental and epileptic encephalopathy

et al. 2020

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“…Until very recently, no genetic variants/mutations in ADARB1 (encoding ADAR2) had been associated with specific diseases. Bi-allelic ADARB1 variants were found in patients with microcephaly, intellectual disability and seizures [ 65 ]. The mutations resulted in a range of changes in ADAR2 expression, with variants affecting splicing and isoform usage and others leading to reduced protein stability.…”

Section: Mammalian A-to-i Rna Editing and Adenosine Deaminase Acting mentioning

confidence: 99%

What do editors do? Understanding the physiological functions of A-to-I RNA editing by adenosine deaminase acting on RNAs

Heraud-Farlow

Walkley

2020

Open Biol.

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Adenosine-to-inosine (A-to-I) editing is a post-transcriptional modification of RNA which changes its sequence, coding potential and secondary structure. Catalysed by the adenosine deaminase acting on RNA (ADAR) proteins, ADAR1 and ADAR2, A-to-I editing occurs at approximately 50 000–150 000 sites in mice and into the millions of sites in humans. The vast majority of A-to-I editing occurs in repetitive elements, accounting for the discrepancy in total numbers of sites between species. The species-conserved primary role of editing by ADAR1 in mammals is to suppress innate immune activation by unedited cell-derived endogenous RNA. In the absence of editing, inverted paired sequences, such as Alu elements, are thought to form stable double-stranded RNA (dsRNA) structures which trigger activation of dsRNA sensors, such as MDA5. A small subset of editing sites are within coding sequences and are evolutionarily conserved across metazoans. Editing by ADAR2 has been demonstrated to be physiologically important for recoding of neurotransmitter receptors in the brain. Furthermore, changes in RNA editing are associated with various pathological states, from the severe autoimmune disease Aicardi-Goutières syndrome, to various neurodevelopmental and psychiatric conditions and cancer. However, does detection of an editing site imply functional importance? Genetic studies in humans and genetically modified mouse models together with evolutionary genomics have begun to clarify the roles of A-to-I editing in vivo . Furthermore, recent developments suggest there may be the potential for distinct functions of editing during pathological conditions such as cancer.

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“…Mislocalization of ADAR was also recently reported in human and mouse models of C9orf72-mediated amyotrophic lateral sclerosis (ALS) (Moore et al, 2019). Common SNPs in the ADAR gene family have also been implicated in numerous diseases including intellectual disability, microcephaly, epilepsy (Tan et al, 2020), hippocampal volume, type II diabetes, and aspects of Alzheimer’s disease and lung cancer (Buniello et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Whole-transcriptome RNA editing analysis in single cortical neurons links locus 15q11 with psychiatric illness

Ansell

Thomas

Bonelli

et al. 2019

Preprint

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11Conversion of adenosine to inosine in RNA by ADAR enzymes occurs at thousands of sites in the human transcriptome, and is 12 essential for healthy brain development. This process, known as 'RNA editing', is dysregulated in many neuropsychiatric 13 diseases, but is little understood at the level of individual neurons. We examined full-length nuclear transcriptomes of 3,055 14 neurons from six cortical regions of a neurotypical post-mortem female donor and identified 40,861 high-confidence edited 15 sites. The majority of sites were located within Alu repeats in introns or 3' UTRs, and were present in previously published RNA 16 editing databases. We identified 15,784 putative novel RNA editing sites, 30% of which were also detectable in independently 17 generated neuronal transcriptomes from unrelated donors. The strongest correlates of global editing rates were expression 18 levels of small nucleolar RNAs from the SNORD115 and SNORD116 cluster (15q11), known to modulate serotonin receptor 19 processing and to colocalize with ADAR2, one of three known RNA editing enzymes in humans. As expected, expression of 20 DNA and RNA binding proteins were negatively associated with editing. We present evidence for dysregulated RNA editing in 21 six rare genetic conditions; and report 117 differentially edited sites between cortical regions and neuronal subtypes. These 22 results provide spatial and neurophenotypic context for 1,871 and 998 sites that are differentially edited in the brains of 23 schizophrenic and autistic patients respectively, and a reference for future studies of RNA editing in single brain cells from 24 these cohorts. 2526 29 conversion of adenosine to inosine (A>I) in nascent RNA transcripts by ADAR1 and ADAR2 enzymes, known as 'RNA editing', is 30 the most abundant RNA modification in the primate central nervous system, and confers transcriptomic diversity beyond that 31 encoded in the genome [1]. RNA editing is essential for healthy brain development and increases with age [2]. 32 33 Dysregulated editing is implicated in epilepsy [3], glioblastoma [4], major depression [5], autism spectrum disorder [6] and 34 schizophrenia [7]. ADAR1 primarily edits adenosine within repetitive regions; ADAR2 primarily edits non-repetitive regions, and 35ADAR3 is a catalytically inactive inhibitor of editing [8]. ADAR2-null mice die in utero and partial knock-out neonatal animals 36 succumb to severe seizures [9]. In humans, mutations in ADAR1 cause skin dyschromatosis (MIM 127400) and Aicardi-Goutieres 37 encephalopathy (MIM 615010) with sub-types including striatal and motor neurodegeneration [10,11]. Mislocalization of ADAR 38 was recently discovered in human and mouse models of C9orf72-mediated amyotrophic lateral sclerosis (ALS) [12]. Common 39SNPs in this gene family are also implicated in 18 complex human traits including hippocampal volume, type II diabetes, and 40 aspects of Alzheimer's disease and lung cancer [13]. 42Recently thousands of edited sites were identified in bulk RNA sequencing of human tissues [...

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

Cited by 34 publications

References 73 publications

Biallelic variants in ADARB1, encoding a dsRNA-specific adenosine deaminase, cause a severe developmental and epileptic encephalopathy

Biallelic variants in ADARB1, encoding a dsRNA-specific adenosine deaminase, cause a severe developmental and epileptic encephalopathy

What do editors do? Understanding the physiological functions of A-to-I RNA editing by adenosine deaminase acting on RNAs

Whole-transcriptome RNA editing analysis in single cortical neurons links locus 15q11 with psychiatric illness

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