Germline AGO2 mutations impair RNA interference and human neurological 
development

Lessel, Davor; Zeitler, Daniela M.; Reijnders, Margot R. F.; Kazantsev, Andriy; Hassani Nia, Fatemeh; Bartholomäus, Alexander; Martens, Victoria; Bruckmann, Astrid; Graus, Veronika; McConkie-Rosell, Allyn; McDonald, Marie; Lozic, Bernarda; Tan, Ee-Shien; Gerkes, Erica; Johannsen, Jessika; Denecke, Jonas; Telegrafi, Aida; Zonneveld-Huijssoon, Evelien; Lemmink, Henny H.; Cham, Breana W. M.; Kovacevic, Tanja; Ramsdell, Linda; Foss, Kimberly; Le Duc, Diana; Mitter, Diana; Syrbe, Steffen; Merkenschlager, Andreas; Sinnema, Margje; Panis, Bianca; Lazier, Joanna; Osmond, Matthew; Hartley, Taila; Mortreux, Jeremie; Busa, Tiffany; Missirian, Chantal; Prasun, Pankaj; Lüttgen, Sabine; Mannucci, Ilaria; Lessel, Ivana; Schob, Claudia; Kindler, Stefan; Pappas, John; Rabin, Rachel; Willemsen, Marjolein; Gardeitchik, Thatjana; Löhner, Katharina; Rump, Patrick; Dias, Kerith-Rae; Evans, Carey-Anne; Andrews, Peter Ian; Roscioli, Tony; Brunner, Han G.; Chijiwa, Chieko; Lewis, M. E. Suzanne; Jamra, Rami Abou; Dyment, David A.; Boycott, Kym M.; Stegmann, Alexander P. A.; Kubisch, Christian; Tan, Ene-Choo; Mirzaa, Ghayda M.; McWalter, Kirsty; Kleefstra, Tjitske; Pfundt, Rolph; Ignatova, Zoya; Meister, Gunter; Kreienkamp, Hans-Jürgen

doi:10.1038/s41467-020-19572-5

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Journal Article

Germline AGO2 mutations impair RNA interference and human neurological development

Authors

Lessel, Davor
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Zeitler, Daniela M.
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Reijnders, Margot R. F.
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Kazantsev, Andriy
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Hassani Nia, Fatemeh
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Bartholomäus, Alexander
3.7 Geomicrobiology, 3.0 Geochemistry, Departments, GFZ Publication Database, Deutsches GeoForschungsZentrum;

Martens, Victoria
External Organizations;

Bruckmann, Astrid
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Graus, Veronika
External Organizations;

McConkie-Rosell, Allyn
External Organizations;

McDonald, Marie
External Organizations;

Lozic, Bernarda
External Organizations;

Tan, Ee-Shien
External Organizations;

Gerkes, Erica
External Organizations;

Johannsen, Jessika
External Organizations;

Denecke, Jonas
External Organizations;

Telegrafi, Aida
External Organizations;

Zonneveld-Huijssoon, Evelien
External Organizations;

Lemmink, Henny H.
External Organizations;

Cham, Breana W. M.
External Organizations;

Kovacevic, Tanja
External Organizations;

Ramsdell, Linda
External Organizations;

Foss, Kimberly
External Organizations;

Le Duc, Diana
External Organizations;

Mitter, Diana
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Syrbe, Steffen
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Merkenschlager, Andreas
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Sinnema, Margje
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Panis, Bianca
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Lazier, Joanna
External Organizations;

Osmond, Matthew
External Organizations;

Hartley, Taila
External Organizations;

Mortreux, Jeremie
External Organizations;

Busa, Tiffany
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Missirian, Chantal
External Organizations;

Prasun, Pankaj
External Organizations;

Lüttgen, Sabine
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Mannucci, Ilaria
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Lessel, Ivana
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Schob, Claudia
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Kindler, Stefan
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Pappas, John
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Rabin, Rachel
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Willemsen, Marjolein
External Organizations;

Gardeitchik, Thatjana
External Organizations;

Löhner, Katharina
External Organizations;

Rump, Patrick
External Organizations;

Dias, Kerith-Rae
External Organizations;

Evans, Carey-Anne
External Organizations;

Andrews, Peter Ian
External Organizations;

Roscioli, Tony
External Organizations;

Brunner, Han G.
External Organizations;

Chijiwa, Chieko
External Organizations;

Lewis, M. E. Suzanne
External Organizations;

Jamra, Rami Abou
External Organizations;

Dyment, David A.
External Organizations;

Boycott, Kym M.
External Organizations;

Stegmann, Alexander P. A.
External Organizations;

Kubisch, Christian
External Organizations;

Tan, Ene-Choo
External Organizations;

Mirzaa, Ghayda M.
External Organizations;

McWalter, Kirsty
External Organizations;

Kleefstra, Tjitske
External Organizations;

Pfundt, Rolph
External Organizations;

Ignatova, Zoya
External Organizations;

Meister, Gunter
External Organizations;

Kreienkamp, Hans-Jürgen
External Organizations;

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Citation

Lessel, D., Zeitler, D. M., Reijnders, M. R. F., Kazantsev, A., Hassani Nia, F., Bartholomäus, A., Martens, V., Bruckmann, A., Graus, V., McConkie-Rosell, A., McDonald, M., Lozic, B., Tan, E.-S., Gerkes, E., Johannsen, J., Denecke, J., Telegrafi, A., Zonneveld-Huijssoon, E., Lemmink, H. H., Cham, B. W. M., Kovacevic, T., Ramsdell, L., Foss, K., Le Duc, D., Mitter, D., Syrbe, S., Merkenschlager, A., Sinnema, M., Panis, B., Lazier, J., Osmond, M., Hartley, T., Mortreux, J., Busa, T., Missirian, C., Prasun, P., Lüttgen, S., Mannucci, I., Lessel, I., Schob, C., Kindler, S., Pappas, J., Rabin, R., Willemsen, M., Gardeitchik, T., Löhner, K., Rump, P., Dias, K.-R., Evans, C.-A., Andrews, P. I., Roscioli, T., Brunner, H. G., Chijiwa, C., Lewis, M. E. S., Jamra, R. A., Dyment, D. A., Boycott, K. M., Stegmann, A. P. A., Kubisch, C., Tan, E.-C., Mirzaa, G. M., McWalter, K., Kleefstra, T., Pfundt, R., Ignatova, Z., Meister, G., Kreienkamp, H.-J. (2020): Germline AGO2 mutations impair RNA interference and human neurological development. - Nature Communications, 11, 5797.
https://doi.org/10.1038/s41467-020-19572-5

Cite as: https://gfzpublic.gfz-potsdam.de/pubman/item/item_5004000

Abstract

ARGONAUTE-2 and associated miRNAs form the RNA-induced silencing complex (RISC), which targets mRNAs for translational silencing and degradation as part of the RNA interference pathway. Despite the essential nature of this process for cellular function, there is little information on the role of RISC components in human development and organ function. We identify 13 heterozygous mutations in AGO2 in 21 patients affected by disturbances in neurological development. Each of the identified single amino acid mutations result in impaired shRNA-mediated silencing. We observe either impaired RISC formation or increased binding of AGO2 to mRNA targets as mutation specific functional consequences. The latter is supported by decreased phosphorylation of a C-terminal serine cluster involved in mRNA target release, increased formation of dendritic P-bodies in neurons and global transcriptome alterations in patient-derived primary fibroblasts. Our data emphasize the importance of gene expression regulation through the dynamic AGO2-RNA association for human neuronal development.