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

  title={Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2},
  author={Miyoko Higuchi and Stefan Maas and Frank N. Single and Jochen C. Hartner and Andrei Rozov and Nail Burnashev and Dirk Feldmeyer and Rolf Sprengel and P. H. Seeburg},
RNA editing by site-selective deamination of adenosine to inosine alters codons and splicing in nuclear transcripts, and therefore protein function. ADAR2 (refs 7, 8) is a candidate mammalian editing enzyme that is widely expressed in brain and other tissues, but its RNA substrates are unknown. Here we have studied ADAR2-mediated RNA editing by generating mice that are homozygous for a targeted functional null allele. Editing in ADAR2-/- mice was substantially reduced at most of 25 positions in… 

Requirement of the RNA-editing Enzyme ADAR2 for Normal Physiology in Mice*

Extended phenotypic analysis covering ∼320 parameters identified significant changes related to absence of ADAR2 in behavior, hearing ability, allergy parameters and transcript profiles of brain.

The ADAR RNA editing enzyme controls neuronal excitability in Drosophila melanogaster

It is demonstrated that neuronal excitability is linked to dADAR expression levels in individual neurons; Adar-overexpressing larval motor neurons show reduced excitability whereas Adar5G1 null mutant or targeted Adar knockdown motor neurons exhibit increased excitability.

Altered RNA Editing in Mice Lacking ADAR2 Autoregulation

It is demonstrated that ADAR2 autoediting and subsequent alternative splicing are abolished in homozygous ΔECS mice and that ADar2 protein expression is increased in numerous tissues compared to wild-type animals, indicating thatADAR2Autoediting is a key regulator of ADAR1 protein expression and activity in vivo.

Glutamate receptor RNA editing in health and disease

Overall, these data indicate that a highly regulated process of glutamate receptor editing is of key importance in the proper function of neuronal cells and in their ability to adapt and modulate synaptic function.

ADAR2 affects mRNA coding sequence edits with only modest effects on gene expression or splicing in vivo

This work illustrates that ADAR2 is important in site-specific changes of protein coding sequences but has relatively modest effects on gene expression and splicing in the adult mouse frontal cortex.

Tuning of RNA editing by ADAR is required in Drosophila

It is shown that editing restricts ADAR function since the edited isoform of ADAR is less active in vitro and in vivo than the genome‐encoded, unedited isoform.

RNA editing in regulating gene expression in the brain.

Stress-induced Apoptosis Associated with Null Mutation of ADAR1 RNA Editing Deaminase Gene*

The results demonstrate an essential requirement for ADAR1 in embryogenesis and suggest that it functions to promote survival of numerous tissues by editing one or more double-stranded RNAs required for protection against stress-induced apoptosis.

Regulation of glutamate receptor B pre-mRNA splicing by RNA editing

By comparing the events at the Q/R and R/G sites, it is shown that editing can both stimulate and repress splicing efficiency, and that only properly edited mRNAs become spliced and exported to the cytoplasm.



A mammalian RNA editing enzyme

The cloning of complementary DNA for RED1, a dsRNA adenosine deaminase expressed in brain and peripheral tissues that efficiently edits the Q/R site in GluR-B pre-mRNA in vitro is reported, indicating that members of an emerging gene family catalyse adenosines deamination in nuclear transcripts with distinct but overlapping substrate specificities.

Early-Onset Epilepsy and Postnatal Lethality Associated with an Editing-Deficient GluR-B Allele in Mice

The arginine residue at position 586 of the GluR-B subunit renders heteromeric α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)-sensitive glutamate receptor channels impermeable to calcium.

Q/R site editing in kainate receptor GluR5 and GluR6 pre-mRNAs requires distant intronic sequences.

RNA editing by adenosine deamination in brain-expressed pre-mRNAs for glutamate receptor (GluR) subunits alters gene-specified codons for functionally critical positions, such as the channel's Q/R

Structural Requirements for RNA Editing in Glutamate Receptor Pre-mRNAs by Recombinant Double-stranded RNA Adenosine Deaminase (*)

It is shown here that DRADA indeed edits GluR pre-mRNAs, but that it displays selectivity for certain editing sites, and that this substrate selectivity correlated with the base pairing status and sequence environment of the editing-targeted adenosines.

Editing of the GLuR‐B ion channel RNA in vitro by recombinant double‐stranded RNA adenosine deaminase.

It is demonstrated in vitro that DRADA is indeed involved in editing of the GLuR‐B RNA and the Q/R site‐selective editing by DRADA requires a cofactor protein(s) commonly present even in non‐neuronal cells.

Adenosine-to-Inosine Conversion in mRNA

This chapter describes a number of mRNA substrates that undergo A-to-I editing events, the effects that such alterations in coding potential have upon protein function, and the candidate enzymes responsible for such posttranscriptional modifications.

Regulation of alternative splicing by RNA editing

Observations indicate that RNA editing can serve as a mechanism for regulating alternative splicing and they suggest a novel strategy by which ADAR2 can modulate its own expression.

Editing of glutamate receptor B subunit ion channel RNAs by four alternatively spliced DRADA2 double-stranded RNA adenosine deaminases

Isoforms DRADA2c and -2d, which have a distinctive truncated shorter C-terminal structure, displayed weak adenosine-to-inosine conversion activity but no editing activity tested at three known sites of GluR-B RNA, possible role in the regulatory mechanism of RNA editing is discussed.