Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2

Higuchi, Miyoko; Maas, Stefan; Single, Frank Nicolai; Hartner, Jochen C.; Rozov, Andrej; Burnashev, Nail; Feldmeyer, Dirk; Sprengel, Rolf; Seeburg, Peter H.

doi:10.1038/35017558

Cited by 879 publications

(983 citation statements)

References 24 publications

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“…Comparing the intron-exon junction of unedited, partially edited or fully edited Flnb transcripts to the consensus 5′ splice site sequences clearly showed that RNA editing decreases the probability of a Flnb transcript of being spliced. It seems therefore plausible that edited Flnb transcripts are less efficiently spliced, a phenomenon already reported by us and others [32,33]. …”

Section: Discussionsupporting

confidence: 56%

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Organ-wide profiling in mouse reveals high editing levels of Filamin B mRNA in the musculoskeletal system

et al. 2018

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Adenosine to inosine RNA editing in protein-coding messenger RNAs (mRNAs) potentially leads to changes in the amino acid composition of the encoded proteins. The mRNAs encoding the ubiquitously expressed actin-crosslinking proteins Filamin A and Filamin B undergo RNA editing leading to a highly conserved glutamine to arginine exchange at the identical position in either protein. Here, by targeted amplicon sequencing we analysed the RNA editing of Filamin B across several mouse tissues during post-natal development. We find highest filamin B editing levels in skeletal muscles, cartilage and bones, tissues where Filamin B function seems most important. Through the analysis of Filamin B editing in mice deficient in either ADAR1 or 2, we identified ADAR2 as the enzyme responsible for Filamin B RNA editing. We show that in neuronal tissues Filamin B editing drops in spliced transcripts indicating regulated maturation of edited transcripts. We show further that the variability of Filamin B editing across several organs correlates with its mRNA expression.

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Section: Discussionsupporting

confidence: 56%

“…Cerebral cortices of rescued ADAR1 knockout [6] and ADAR2 knockout [32] mice were dissected at day 15 after birth and snap frozen in liquid nitrogen; wild type littermates were used as control. For further analysis on different tissues adult (> P120) ADAR2 knockout mice were used.…”

Section: Methodsmentioning

confidence: 99%

Organ-wide profiling in mouse reveals high editing levels of Filamin B mRNA in the musculoskeletal system

et al. 2018

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“…Mice with a homozygous Adar2-null mutation die several weeks after birth. These mice experience repeated episodes of epileptic seizures that originate from excess influx of Ca 2+ and consequent neuronal death caused by under-editing of GluR2 pre-mRNA at the Q/R site 59 , which is a major target of ADAR2 (FIG. 3a).…”

Section: Rna-editing Deficienciesmentioning

confidence: 99%

Editor meets silencer: crosstalk between RNA editing and RNA interference

Nishikura

2006

Nat Rev Mol Cell Biol

257

263

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The most prevalent type of RNA editing is mediated by ADAR (adenosine deaminase acting on RNA) enzymes, which convert adenosines to inosines (a process known as A→I RNA editing) in double-stranded (ds)RNA substrates. A→I RNA editing was long thought to affect only selected transcripts by altering the proteins they encode. However, genome-wide screening has revealed numerous editing sites within inverted Alu repeats in introns and untranslated regions. Also, recent evidence indicates that A→I RNA editing crosstalks with RNA-interference pathways, which, like A→I RNA editing, involve dsRNAs. A→I RNA editing therefore seems to have additional functions, including the regulation of retrotransposons and gene silencing, which adds a new urgency to the challenges of fully understanding ADAR functions.An RNA transcript is subjected to various maturation processes, such as 5′ capping, splicing, 3′ processing and polyadenylation, after it is transcribed from the gene. Post-transcriptional processing of primary transcripts is essential to generate mature messenger RNAs that are ready to be translated into proteins 1 . RNA editing is a post-transcriptional-processing mechanism that results in an RNA sequence that is different from the one encoded by the genome, and thereby contributes to the diversity of gene products. There are different types of RNA-editing mechanism that either add or delete nucleotides, or that change one nucleotide into another 2 (BOX 1).The type of RNA editing that is most prevalent in higher eukaryotes converts adenosine (A) residues into inosine (I) in double-stranded (ds)RNAs through the action of ADAR (adenosine deaminase acting on RNA) enzymes [3][4][5] . A→I RNA editing of a short dsRNA that has formed between a coding exon and nearby intron sequences can lead to a codon change and an alteration in the protein function. However, it was recently discovered that the most frequent targets of A→I RNA editing seem to be long, but partially double-stranded, RNAs that are formed from inverted Alu repeats and long interspersed element (LINE) repeats located in introns and untranslated regions (UTRs) of mRNAs [6][7][8][9] . Global editing of non-coding RNA might control the expression of genes that harbour these repeat sequences of retrotransposon origin.Post-transcriptional gene regulation can also occur through RNA interference (RNAi), an evolutionarily conserved phenomenon that involves dsRNA molecules 10,11 . Small interfering RNAs (siRNAs) and microRNAs (miRNAs) are non-coding RNAs that are generated by a class of RNase III ribonucleases (specifically, Dicer and Drosha). These small RNAs are incorporated into the RNA-induced silencing complex (RISC), which mediates the RNAi process [12][13][14][15][16] . The idea that the RNAi and A→I RNA editing pathways might compete for a Competing interests statement: The author declares no competing financial interests. [23][24][25] . NIH Public AccessIn this review, I discuss recent findings on new functions of A→I RNA editing in the regulation of non...

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“…This molecular abnormality specifically results from reduced levels of an RNA-editing enzyme called adenosine deaminase acting on RNA 2 (ADAR2) among other members of the ADAR family 13,14 . ADAR2 specifically catalyses adenosine (A) to inosine (I; A-to-I) conversion 15 at the Q/R site of GluA2 pre-mRNA 16 , thereby making AMPA receptors impermeable to Ca 2 þ (ref. 17).…”

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confidence: 99%

A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology

et al. 2012

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Both mislocalization of TDP-43 and downregulation of RNA-editing enzyme ADAR2 colocalize in the motor neurons of amyotrophic lateral sclerosis patients, but how they are linked is not clear. Here we demonstrate that activation of calpain, a Ca 2 þ -dependent cysteine protease, by upregulation of Ca 2 þ -permeable AMPA receptors generates carboxyterminal-cleaved TDP-43 fragments and causes mislocalization of TDP-43 in the motor neurons expressing glutamine/arginine site-unedited GluA2 of conditional ADAR2 knockout (AR2) mice that mimic the amyotrophic lateral sclerosis pathology. These abnormalities are inhibited in the AR2res mice that express Ca 2 þ -impermeable AMPA receptors in the absence of ADAR2 and in the calpastatin transgenic mice, but are exaggerated in the calpastatin knockout mice. Additional demonstration of calpain-dependent TDP43 fragments in the spinal cord and brain of amyotrophic lateral sclerosis patients, and high vulnerability of amyotrophic lateral sclerosis-linked mutant TDP43 to cleavage by calpain support the crucial role of the calpain-dependent cleavage of TDP43 in the amyotrophic lateral sclerosis pathology.

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Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2

Cited by 879 publications

References 24 publications

Organ-wide profiling in mouse reveals high editing levels of Filamin B mRNA in the musculoskeletal system

Organ-wide profiling in mouse reveals high editing levels of Filamin B mRNA in the musculoskeletal system

Editor meets silencer: crosstalk between RNA editing and RNA interference

A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology

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