Germline AGO2 mutations impair RNA interference and human neurological development

Author:

Lessel DavorORCID,Zeitler Daniela M.,Reijnders Margot R. F.ORCID,Kazantsev AndriyORCID,Hassani Nia FatemehORCID,Bartholomäus AlexanderORCID,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 EvelienORCID,Lemmink Henny H.ORCID,Cham Breana W. M.,Kovacevic TanjaORCID,Ramsdell Linda,Foss Kimberly,Le Duc DianaORCID,Mitter Diana,Syrbe Steffen,Merkenschlager AndreasORCID,Sinnema Margje,Panis Bianca,Lazier Joanna,Osmond Matthew,Hartley Taila,Mortreux JeremieORCID,Busa Tiffany,Missirian Chantal,Prasun Pankaj,Lüttgen Sabine,Mannucci IlariaORCID,Lessel Ivana,Schob Claudia,Kindler Stefan,Pappas JohnORCID,Rabin Rachel,Willemsen Marjolein,Gardeitchik Thatjana,Löhner Katharina,Rump PatrickORCID,Dias Kerith-RaeORCID,Evans Carey-Anne,Andrews Peter Ian,Roscioli Tony,Brunner Han G.,Chijiwa Chieko,Lewis M. E. Suzanne,Jamra Rami AbouORCID,Dyment David A.,Boycott Kym M.,Stegmann Alexander P. A.ORCID,Kubisch Christian,Tan Ene-ChooORCID,Mirzaa Ghayda M.ORCID,McWalter KirstyORCID,Kleefstra Tjitske,Pfundt Rolph,Ignatova Zoya,Meister Gunter,Kreienkamp Hans-JürgenORCID

Abstract

AbstractARGONAUTE-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.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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