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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.

SUBMITTER: Lessel D 

PROVIDER: S-EPMC7670403 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Germline AGO2 mutations impair RNA interference and human neurological development.

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

Nature communications 20201116 1


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 a  ...[more]

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