Germline AGO2 mutations impair RNA interference and human neurological development

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

doi:10.1038/s41467-020-19572-5

Germline AGO2 mutations impair RNA interference and human neurological development

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

^*Corresponding author for this work

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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.

Original language	English
Article number	5797
Number of pages	14
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-19572-5
Publication status	Published - 16-Nov-2020

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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., ... Kreienkamp, H-J. (2020). Germline AGO2 mutations impair RNA interference and human neurological development. Nature Communications, 11(1), Article 5797. https://doi.org/10.1038/s41467-020-19572-5

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title = "Germline AGO2 mutations impair RNA interference and human neurological development",

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.",

author = "Davor Lessel and Zeitler, {Daniela M} and Reijnders, {Margot R F} and Andriy Kazantsev and {Hassani Nia}, Fatemeh and Alexander Bartholom{\"a}us 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 Lemmink, {Henny H} and Cham, {Breana W M} and Tanja Kovacevic and Linda Ramsdell and Kimberly Foss and {Le Duc}, Diana 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 L{\"u}ttgen 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 L{\"o}hner and Patrick Rump and Kerith-Rae Dias and Carey-Anne Evans and Andrews, {Peter Ian} and Tony Roscioli and Brunner, {Han G} and Chieko Chijiwa and Lewis, {M E Suzanne} and Jamra, {Rami Abou} and Dyment, {David A} and Boycott, {Kym M} and Stegmann, {Alexander P A} and Christian Kubisch and Ene-Choo Tan and Mirzaa, {Ghayda M} and Kirsty McWalter and Tjitske Kleefstra and Rolph Pfundt and Zoya Ignatova and Gunter Meister and Hans-J{\"u}rgen Kreienkamp",

year = "2020",

month = nov,

day = "16",

doi = "10.1038/s41467-020-19572-5",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

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Lessel, D, Zeitler, DM, Reijnders, MRF, 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, HH, Cham, BWM, 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, PI, Roscioli, T, Brunner, HG, Chijiwa, C, Lewis, MES, Jamra, RA, Dyment, DA, Boycott, KM, Stegmann, APA, Kubisch, C, Tan, E-C, Mirzaa, GM, 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, vol. 11, no. 1, 5797. https://doi.org/10.1038/s41467-020-19572-5

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 - Article

C2 - 33199684

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5797

ER -