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

Author

Listed:
  • Miyoko Higuchi

    (Max-Planck Institute for Medical Research)

  • Stefan Maas

    (Max-Planck Institute for Medical Research
    Massachusetts Institute of Technology)

  • 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)

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.

Suggested Citation

  • Miyoko Higuchi & Stefan Maas & Frank N. Single & Jochen Hartner & Andrei Rozov & Nail Burnashev & Dirk Feldmeyer & Rolf Sprengel & Peter H. Seeburg, 2000. "Point mutation in an AMPA receptor gene rescues lethality in mice deficient in the RNA-editing enzyme ADAR2," Nature, Nature, vol. 406(6791), pages 78-81, July.
    • Handle: RePEc:nat:nature:v:406:y:2000:i:6791:d:10.1038_35017558
    DOI: 10.1038/35017558
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    Cited by:

    1. Liran Carmel & Eugene V Koonin & Stella Dracheva, 2012. "Dependencies among Editing Sites in Serotonin 2C Receptor mRNA," PLOS Computational Biology, Public Library of Science, vol. 8(9), pages 1-13, September.
    2. Winston H. Cuddleston & Junhao Li & Xuanjia Fan & Alexey Kozenkov & Matthew Lalli & Shahrukh Khalique & Stella Dracheva & Eran A. Mukamel & Michael S. Breen, 2022. "Cellular and genetic drivers of RNA editing variation in the human brain," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    3. Katarzyna Niescierowicz & Leszek Pryszcz & Cristina Navarrete & Eugeniusz Tralle & Agata Sulej & Karim Abu Nahia & Marta Elżbieta Kasprzyk & Katarzyna Misztal & Abhishek Pateria & Adrianna Pakuła & Ma, 2022. "Adar-mediated A-to-I editing is required for embryonic patterning and innate immune response regulation in zebrafish," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    4. Xiangbin Ruan & Kaining Hu & Xiaochang Zhang, 2023. "PIE-seq: identifying RNA-binding protein targets by dual RNA-deaminase editing and sequencing," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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