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

Miyoko Higuchi, Stefan Maas, Frank N. Single, Jochen Hartner, Andrei Rozov, Nail Burnashev, Dirk Feldmeyer, Rolf Sprengel and Peter H. Seeburg ()
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Miyoko Higuchi: Max-Planck Institute for Medical Research
Stefan Maas: Max-Planck Institute for Medical Research
Frank N. Single: Max-Planck Institute for Medical Research
Jochen Hartner: Max-Planck Institute for Medical Research
Andrei Rozov: Max-Planck Institute for Medical Research
Nail Burnashev: Max-Planck Institute for Medical Research
Dirk Feldmeyer: Max-Planck Institute for Medical Research
Rolf Sprengel: Max-Planck Institute for Medical Research
Peter H. Seeburg: Max-Planck Institute for Medical Research

Nature, 2000, vol. 406, issue 6791, 78-81

Abstract: Abstract RNA editing by site-selective deamination of adenosine to inosine1,2 alters codons3,4 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 transcripts3,4,5,6; 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 site3,6, 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.

Date: 2000
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DOI: 10.1038/35017558

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