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

RNA editing by site-selective deamination of adenosine to inosine(1,2) alte rs codons(3,4) and splicing(5) in nuclear transcripts(6), and therefore pro tein function. ADAR2 (refs 7, 8) is a candidate mammalian editing enzyme th at is widely expressed in brain and other tissues(7), but its RNA substrate s are unknown. Here we have studied ADAR2-mediated RNA editing by generatin g mice that are homozygous for a targeted functional null allele. Editing i n ADAR2(-/-) mice was substantially reduced at most of 25 positions in dive rse transcripts(3-6); the mutant mice became prone to seizures and died you ng. The impaired phenotype appeared to result entirely from a single undere dited position, as it reverted to normal when both alleles for the underedi ted transcript were substituted with alleles encoding the edited version ex onically(9). The critical position specifies an ion channel determinant(10) , the Q/R site(3,6), in AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole pr opionate) receptor(10) GluR-B pre-messenger RNA. We conclude that this tran script is the physiologically most important substrate of ADAR2.