The Phenotype of the Most Common Human ADAR1p150 Zα Mutation P193A in Mice is Partially Penetrant

Overview

Journal EMBO Rep

Specialty Molecular Biology

Date 2023 Mar 28

PMID 36975179

Authors

Zhen Liang

Alistair M Chalk

Scott Taylor

Ankita Goradia

Jacki E Heraud-Farlow

Carl R Walkley

Affiliations

Soon will be listed here.

Abstract

ADAR1 -mediated A-to-I RNA editing is a self-/non-self-discrimination mechanism for cellular double-stranded RNAs. ADAR mutations are one cause of Aicardi-Goutières Syndrome, an inherited paediatric encephalopathy, classed as a "Type I interferonopathy." The most common ADAR1 mutation is a proline 193 alanine (p.P193A) mutation, mapping to the ADAR1p150 isoform-specific Zα domain. Here, we report the development of an independent murine P195A knock-in mouse, homologous to human P193A. The Adar1 mice are largely normal and the mutation is well tolerated. When the P195A mutation is compounded with an Adar1 null allele (Adar1 ), approximately half the animals are runted with a shortened lifespan while the remaining Adar1 animals are normal, contrasting with previous reports. The phenotype of the Adar1 animals is both associated with the parental genotype and partly non-genetic/environmental. Complementation with an editing-deficient ADAR1 (Adar1 ), or the loss of MDA5, rescues phenotypes in the Adar1 mice.

Citing Articles

The prototypical interferonopathy: Aicardi-Goutières syndrome from bedside to bench.

Hofer M, Modesti N, Coufal N, Wang Q, Sase S, Miner J Immunol Rev. 2024; 327(1):83-99.

PMID: 39473130 PMC: 11672868. DOI: 10.1111/imr.13413.

Neurodegenerative diseases reflect the reciprocal roles played by retroelements in regulating memory and immunity.

Herbert A Front Neurosci. 2024; 18:1445540.

PMID: 39371608 PMC: 11451048. DOI: 10.3389/fnins.2024.1445540.

ADAR1: from basic mechanisms to inhibitors.

Rehwinkel J, Mehdipour P Trends Cell Biol. 2024; 35(1):59-73.

PMID: 39030076 PMC: 11718369. DOI: 10.1016/j.tcb.2024.06.006.

RNA editing and immune control: from mechanism to therapy.

Hu S, Li J Curr Opin Genet Dev. 2024; 86:102195.

PMID: 38643591 PMC: 11162905. DOI: 10.1016/j.gde.2024.102195.

Multifaceted roles of RNA editing enzyme ADAR1 in innate immunity.

Jarmoskaite I, Li J RNA. 2024; 30(5):500-511.

PMID: 38531645 PMC: 11019752. DOI: 10.1261/rna.079953.124.

References

Piechotta M, Wyler E, Ohler U, Landthaler M, Dieterich C . JACUSA: site-specific identification of RNA editing events from replicate sequencing data. BMC Bioinformatics. 2017; 18(1):7. PMC: 5210316. DOI: 10.1186/s12859-016-1432-8. View

Smeets M, DeLuca E, Wall M, Quach J, Chalk A, Deans A . The Rothmund-Thomson syndrome helicase RECQL4 is essential for hematopoiesis. J Clin Invest. 2014; 124(8):3551-65. PMC: 4109528. DOI: 10.1172/JCI75334. View

Newton K, Wickliffe K, Maltzman A, Dugger D, Strasser A, Pham V . RIPK1 inhibits ZBP1-driven necroptosis during development. Nature. 2016; 540(7631):129-133. DOI: 10.1038/nature20559. View

Dickins R, Hemann M, Zilfou J, Simpson D, Ibarra I, Hannon G . Probing tumor phenotypes using stable and regulated synthetic microRNA precursors. Nat Genet. 2005; 37(11):1289-95. DOI: 10.1038/ng1651. View

Kim J, Nakahama T, Yamasaki R, Costa Cruz P, Vongpipatana T, Inoue M . RNA editing at a limited number of sites is sufficient to prevent MDA5 activation in the mouse brain. PLoS Genet. 2021; 17(5):e1009516. PMC: 8118328. DOI: 10.1371/journal.pgen.1009516. View

Zhang T, Yin C, Boyd D, Quarato G, Ingram J, Shubina M . Influenza Virus Z-RNAs Induce ZBP1-Mediated Necroptosis. Cell. 2020; 180(6):1115-1129.e13. PMC: 7153753. DOI: 10.1016/j.cell.2020.02.050. View

Jiao H, Wachsmuth L, Wolf S, Lohmann J, Nagata M, Kaya G . ADAR1 averts fatal type I interferon induction by ZBP1. Nature. 2022; 607(7920):776-783. PMC: 9329096. DOI: 10.1038/s41586-022-04878-9. View

Ivanov A, Memczak S, Wyler E, Torti F, Porath H, Orejuela M . Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals. Cell Rep. 2015; 10(2):170-7. DOI: 10.1016/j.celrep.2014.12.019. View

Liang Z, Chalk A, Taylor S, Goradia A, Heraud-Farlow J, Walkley C . The phenotype of the most common human ADAR1p150 Zα mutation P193A in mice is partially penetrant. EMBO Rep. 2023; 24(5):e55835. PMC: 10157378. DOI: 10.15252/embr.202255835. View

10.

Ramaswami G, Li J . RADAR: a rigorously annotated database of A-to-I RNA editing. Nucleic Acids Res. 2013; 42(Database issue):D109-13. PMC: 3965033. DOI: 10.1093/nar/gkt996. View

11.

Maurano M, Snyder J, Connelly C, Henao-Mejia J, Sidrauski C, Stetson D . Protein kinase R and the integrated stress response drive immunopathology caused by mutations in the RNA deaminase ADAR1. Immunity. 2021; 54(9):1948-1960.e5. PMC: 8446335. DOI: 10.1016/j.immuni.2021.07.001. View

12.

Singbrant S, Russell M, Jovic T, Liddicoat B, Izon D, Purton L . Erythropoietin couples erythropoiesis, B-lymphopoiesis, and bone homeostasis within the bone marrow microenvironment. Blood. 2011; 117(21):5631-42. DOI: 10.1182/blood-2010-11-320564. View

13.

Kawahara Y, Zinshteyn B, Chendrimada T, Shiekhattar R, Nishikura K . RNA editing of the microRNA-151 precursor blocks cleavage by the Dicer-TRBP complex. EMBO Rep. 2007; 8(8):763-9. PMC: 1978079. DOI: 10.1038/sj.embor.7401011. View

14.

Ward S, George C, Welch M, Liou L, Hahm B, Lewicki H . RNA editing enzyme adenosine deaminase is a restriction factor for controlling measles virus replication that also is required for embryogenesis. Proc Natl Acad Sci U S A. 2010; 108(1):331-6. PMC: 3017198. DOI: 10.1073/pnas.1017241108. View

15.

Ventura A, Kirsch D, McLaughlin M, Tuveson D, Grimm J, Lintault L . Restoration of p53 function leads to tumour regression in vivo. Nature. 2007; 445(7128):661-5. DOI: 10.1038/nature05541. View

16.

Nakahama T, Kawahara Y . Deciphering the Biological Significance of ADAR1-Z-RNA Interactions. Int J Mol Sci. 2021; 22(21). PMC: 8584189. DOI: 10.3390/ijms222111435. View

17.

Rice G, Kasher P, Forte G, Mannion N, Greenwood S, Szynkiewicz M . Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature. Nat Genet. 2012; 44(11):1243-8. PMC: 4154508. DOI: 10.1038/ng.2414. View

18.

Hartner J, Schmittwolf C, Kispert A, Muller A, Higuchi M, Seeburg P . Liver disintegration in the mouse embryo caused by deficiency in the RNA-editing enzyme ADAR1. J Biol Chem. 2003; 279(6):4894-902. DOI: 10.1074/jbc.M311347200. View

19.

Inoue M, Nakahama T, Yamasaki R, Shibuya T, Kim J, Todo H . An Aicardi-Goutières Syndrome-Causative Point Mutation in Gene Invokes Multiorgan Inflammation and Late-Onset Encephalopathy in Mice. J Immunol. 2021; 207(12):3016-3027. DOI: 10.4049/jimmunol.2100526. View

20.

Stellos K, Gatsiou A, Stamatelopoulos K, Matic L, John D, Lunella F . Adenosine-to-inosine RNA editing controls cathepsin S expression in atherosclerosis by enabling HuR-mediated post-transcriptional regulation. Nat Med. 2016; 22(10):1140-1150. DOI: 10.1038/nm.4172. View