Germline AGO2 mutations impair RNA interference and human neurological development
Standard
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.
in: NAT COMMUN, Jahrgang 11, Nr. 1, 16.11.2020, S. 5797.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Germline AGO2 mutations impair RNA interference and human neurological development
AU - Lessel, Davor
AU - Zeitler, Daniela M
AU - Reijnders, Margot R F
AU - Kazantsev, Andriy
AU - Hassani Nia, Fatemeh
AU - Bartholomäus, Alexander
AU - Martens, Victoria
AU - Bruckmann, Astrid
AU - Graus, Veronika
AU - McConkie-Rosell, Allyn
AU - McDonald, Marie
AU - Lozic, Bernarda
AU - Tan, Ee-Shien
AU - Gerkes, Erica
AU - Johannsen, Jessika
AU - Denecke, Jonas
AU - Telegrafi, Aida
AU - Zonneveld-Huijssoon, Evelien
AU - Lemmink, Henny H
AU - Cham, Breana W M
AU - Kovacevic, Tanja
AU - Ramsdell, Linda
AU - Foss, Kimberly
AU - Le Duc, Diana
AU - Mitter, Diana
AU - Syrbe, Steffen
AU - Merkenschlager, Andreas
AU - Sinnema, Margje
AU - Panis, Bianca
AU - Lazier, Joanna
AU - Osmond, Matthew
AU - Hartley, Taila
AU - Mortreux, Jeremie
AU - Busa, Tiffany
AU - Missirian, Chantal
AU - Prasun, Pankaj
AU - Lüttgen, Sabine
AU - Mannucci, Ilaria
AU - Lessel, Ivana
AU - Schob, Claudia
AU - Kindler, Stefan
AU - Pappas, John
AU - Rabin, Rachel
AU - Willemsen, Marjolein
AU - Gardeitchik, Thatjana
AU - Löhner, Katharina
AU - Rump, Patrick
AU - Dias, Kerith-Rae
AU - Evans, Carey-Anne
AU - Andrews, Peter Ian
AU - Roscioli, Tony
AU - Brunner, Han G
AU - Chijiwa, Chieko
AU - Lewis, M E Suzanne
AU - Jamra, Rami Abou
AU - Dyment, David A
AU - Boycott, Kym M
AU - Stegmann, Alexander P A
AU - Kubisch, Christian
AU - Tan, Ene-Choo
AU - Mirzaa, Ghayda M
AU - McWalter, Kirsty
AU - Kleefstra, Tjitske
AU - Pfundt, Rolph
AU - Ignatova, Zoya
AU - Meister, Gunter
AU - Kreienkamp, Hans-Jürgen
PY - 2020/11/16
Y1 - 2020/11/16
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-020-19572-5
DO - 10.1038/s41467-020-19572-5
M3 - SCORING: Journal article
C2 - 33199684
VL - 11
SP - 5797
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
IS - 1
ER -