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

Abstract

RNA editing by site-selective deamination of adenosine to inosine^1,2 alters codons^3,4 and splicing⁵ in nuclear transcripts⁶, and therefore protein function. ADAR2 (refs 7, 8) is a candidate mammalian editing enzyme that is widely expressed in brain and other tissues⁷, 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 diverse transcripts^3,4,5,6; the mutant mice became prone to seizures and died young. The impaired phenotype appeared to result entirely from a single underedited position, as it reverted to normal when both alleles for the underedited transcript were substituted with alleles encoding the edited version exonically⁹. The critical position specifies an ion channel determinant¹⁰, the Q/R site^3,6, in AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionate) receptor¹⁰ GluR-B pre-messenger RNA. We conclude that this transcript is the physiologically most important substrate of ADAR2.