1. Departments of Molecular Neurobiology and
2. Cell Physiology, Max-Planck Institute for Medical Research, Jahnstrasse 29, 69120 Heidelberg, Germany
3. These authors contributed equally to this work
4. Present address: Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue , MA 02139, USA.

Correspondence to: Peter H. Seeburg¹ Correspondence and requests for materials should be addressed to P.H.S. (e-mail: Email: seeburg@mpimf-heidelberg.mpg.de).

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 (-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.