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Germline AGO2 mutations impair RNA interference and human neurological development. 2020
Davor Lessel, and
Daniela M Zeitler, and
Margot R F Reijnders, and
Andriy Kazantsev, and
Fatemeh Hassani Nia, and
Alexander Bartholomäus, and
Victoria Martens, and
Astrid Bruckmann, and
Veronika Graus, and
Allyn McConkie-Rosell, and
Marie McDonald, and
Bernarda Lozic, and
Ee-Shien Tan, and
Erica Gerkes, and
Jessika Johannsen, and
Jonas Denecke, and
Aida Telegrafi, and
Evelien Zonneveld-Huijssoon, and
Henny H Lemmink, and
Breana W M Cham, and
Tanja Kovacevic, and
Linda Ramsdell, and
Kimberly Foss, and
Diana Le Duc, and
Diana Mitter, and
Steffen Syrbe, and
Andreas Merkenschlager, and
Margje Sinnema, and
Bianca Panis, and
Joanna Lazier, and
Matthew Osmond, and
Taila Hartley, and
Jeremie Mortreux, and
Tiffany Busa, and
Chantal Missirian, and
Pankaj Prasun, and
Sabine Lüttgen, and
Ilaria Mannucci, and
Ivana Lessel, and
Claudia Schob, and
Stefan Kindler, and
John Pappas, and
Rachel Rabin, and
Marjolein Willemsen, and
Thatjana Gardeitchik, and
Katharina Löhner, and
Patrick Rump, and
Kerith-Rae Dias, and
Carey-Anne Evans, and
Peter Ian Andrews, and
Tony Roscioli, and
Han G Brunner, and
Chieko Chijiwa, and
M E Suzanne Lewis, and
Rami Abou Jamra, and
David A Dyment, and
Kym M Boycott, and
Alexander P A Stegmann, and
Christian Kubisch, and
Ene-Choo Tan, and
Ghayda M Mirzaa, and
Kirsty McWalter, and
Tjitske Kleefstra, and
Rolph Pfundt, and
Zoya Ignatova, and
Gunter Meister, and
Hans-Jürgen Kreienkamp
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246, Hamburg, Germany. d.lessel@uke.de.
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.
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Evelien Zonneveld-Huijssoon, and
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Steffen Syrbe, and
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Taila Hartley, and
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Chantal Missirian, and
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Sabine Lüttgen, and
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Marjolein Willemsen, and
Thatjana Gardeitchik, and
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Carey-Anne Evans, and
Peter Ian Andrews, and
Tony Roscioli, and
Han G Brunner, and
Chieko Chijiwa, and
M E Suzanne Lewis, and
Rami Abou Jamra, and
David A Dyment, and
Kym M Boycott, and
Alexander P A Stegmann, and
Christian Kubisch, and
Ene-Choo Tan, and
Ghayda M Mirzaa, and
Kirsty McWalter, and
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Victoria Martens, and
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Marie McDonald, and
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Ee-Shien Tan, and
Erica Gerkes, and
Jessika Johannsen, and
Jonas Denecke, and
Aida Telegrafi, and
Evelien Zonneveld-Huijssoon, and
Henny H Lemmink, and
Breana W M Cham, and
Tanja Kovacevic, and
Linda Ramsdell, and
Kimberly Foss, and
Diana Le Duc, and
Diana Mitter, and
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Margje Sinnema, and
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Taila Hartley, and
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Sabine Lüttgen, and
Ilaria Mannucci, and
Ivana Lessel, and
Claudia Schob, and
Stefan Kindler, and
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Chieko Chijiwa, and
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Kym M Boycott, and
Alexander P A Stegmann, and
Christian Kubisch, and
Ene-Choo Tan, and
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Kirsty McWalter, and
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Veronika Graus, and
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Marie McDonald, and
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Ee-Shien Tan, and
Erica Gerkes, and
Jessika Johannsen, and
Jonas Denecke, and
Aida Telegrafi, and
Evelien Zonneveld-Huijssoon, and
Henny H Lemmink, and
Breana W M Cham, and
Tanja Kovacevic, and
Linda Ramsdell, and
Kimberly Foss, and
Diana Le Duc, and
Diana Mitter, and
Steffen Syrbe, and
Andreas Merkenschlager, and
Margje Sinnema, and
Bianca Panis, and
Joanna Lazier, and
Matthew Osmond, and
Taila Hartley, and
Jeremie Mortreux, and
Tiffany Busa, and
Chantal Missirian, and
Pankaj Prasun, and
Sabine Lüttgen, and
Ilaria Mannucci, and
Ivana Lessel, and
Claudia Schob, and
Stefan Kindler, and
John Pappas, and
Rachel Rabin, and
Marjolein Willemsen, and
Thatjana Gardeitchik, and
Katharina Löhner, and
Patrick Rump, and
Kerith-Rae Dias, and
Carey-Anne Evans, and
Peter Ian Andrews, and
Tony Roscioli, and
Han G Brunner, and
Chieko Chijiwa, and
M E Suzanne Lewis, and
Rami Abou Jamra, and
David A Dyment, and
Kym M Boycott, and
Alexander P A Stegmann, and
Christian Kubisch, and
Ene-Choo Tan, and
Ghayda M Mirzaa, and
Kirsty McWalter, and
Tjitske Kleefstra, and
Rolph Pfundt, and
Zoya Ignatova, and
Gunter Meister, and
Hans-Jürgen Kreienkamp
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Journal of internal medicine,
