Adenosine-to-inosine RNA editing and human disease

Abstract

A-to-I RNA editing is a post-transcriptional modification that converts adenosines to inosines in both coding and noncoding RNA transcripts. It is catalyzed by ADAR (adenosine deaminase acting on RNA) enzymes, which exist throughout the body but are most prevalent in the central nervous system. Inosines exhibit properties that are most similar to those of guanosines. As a result, ADAR-mediated editing can post-transcriptionally alter codons, introduce or remove splice sites, or affect the base pairing of the RNA molecule with itself or with other RNAs. A-to-I editing is a mechanism that regulates and diversifies the transcriptome, but the full biological significance of ADARs is not understood. ADARs are highly conserved across vertebrates and are essential for normal development in mammals. Aberrant ADAR activity has been associated with a wide range of human diseases, including cancer, neurological disorders, metabolic diseases, viral infections and autoimmune disorders. ADARs have been shown to contribute to disease pathologies by editing of glutamate receptors, editing of serotonin receptors, mutations in ADAR genes, and by other mechanisms, including recently identified regulatory roles in microRNA processing. Advances in research into many of these diseases may depend on an improved understanding of the biological functions of ADARs. Here, we review recent studies investigating connections between ADAR-mediated RNA editing and human diseases.

Figure 1

Adenosine deamination and the ADAR enzyme family. (a) ADAR enzymes catalyze the A-to-I hydrolytic deamination reaction, by which an adenosine loses an amine group and is converted to inosine. (b) There are four main proteins of the ADAR enzyme family: two isoforms of ADAR1 (p110 and p150), ADAR2 and ADAR3. All of these enzymes contain a conserved deaminase domain, shown in blue. The double-stranded (ds)RNA-binding domains, shown in purple, determine substrate specificity. The two ADAR1 isoforms differ in their Z-DNA-binding domains, shown in green. ADAR3 contains an arginine-rich domain, shown in pink, which binds single-stranded RNA.

Figure 2

ADAR-mediated editing of the GluA2 subunit of the mammalian AMPA receptor. (a) The unedited GluA2 subunit contains a glutamine residue (Q) at the Q/R site (left). ADAR2 can mediate editing of the Q/R site, resulting in a GluA2 subunit that has a positively charged arginine residue (right). (b) When the tetrameric AMPA receptor contains only the unedited form of the GluA2 subunit (light green), the receptor facilitates the flow of calcium ions (left). Incorporation of an edited GluA2 subunit (light green) sharply reduces the calcium permeability of the receptor because of the presence of the large, positive arginine residue (right).

Figure 3

ADAR-mediated editing sites of the mammalian 5-HT_2CR, serotonin receptor. In the 5-HT_2CR pre-mRNA, exon 5 (black text) is bound to the untranslated intron 5 (gray text) and contains ADAR-mediated editing sites A to E (colored in red, blue or purple). Sites A and B (red) are edited selectively by ADAR1 and can produce four codons that encode three distinct amino acids (red box). Site D (blue) is edited preferentially by ADAR2 and can produce two codons that encode two distinct amino acids (blue box). Sites C and E (purple) can be edited by either ADAR1 or ADAR2 and can produce four codons that encode four distinct amino acids (purple box). Editing of these sites can cause various amino acid substitutions, detailed in boxes below the RNA segment. Editing of these sites affects G-protein coupling and serotonin sensitivity. Modified from [36] with permission (RNA Biology).

Figure 4

Mutations in the ADAR1 gene that are associated with human disease. The ADAR1 protein contains several distinct domains (labeled and colored in green, purple, or blue). A number of nucleotide mutations of the ADAR1 gene have been associated with human diseases. There are 130 mutations associated with dyschromatosis symmetrica hereditaria (blue), eight mutations associated with Aicardi-Goutières syndrome (red), and 1 mutation associated with both conditions (black and bold). Many of these mutations occur within key domain regions (indicated by lines from each domain to the first and the last mutation falling within that domain), with the majority of the mutations occurring in the catalytic deaminase domain. dsRNA, double-stranded RNA.