DESCRIPTION:

ARGONAUTE-2 (AGO2) and associated miRNAs form the RNA-induced silencing complex (RISC), that targets mRNAs for translational silencing and degradation, as part of the RNA interference pathway. RNA sequencing was performed of primary dermal fibroblasts obtained from two patients bearing the p.L192P (cases 2 and 3) and one patient with the p.A367P mutation (case 14). The researchers compared the expression patterns of the protein coding transcripts to fibroblasts from age-matched individuals, who were either unaffected or bear a causative mutation unrelated to AGO2. Expression values were calculated by the method detailed in 'HBA-DEALS: accurate and simultaneous identification of differential expression and splicing using hierarchical Bayesian analysis' (Genome Biol. 2020, PMID: 32660516), and log base 2 of the fold change are presented with a FDR of <0.05. Down regulated genes were annotated as Ensembl gene ids. SRA Study id SRP233483. Cell Line Ontology CLO:0037302; Primary Human Dermal Fibroblasts.

LABEL:

Down regulated genes from fibrolbasts of AGO2 mutation patients compared to age-matched individuals

SCORE TYPE:

Effect

DATE ADDED:

2023-06-19

DATE UPDATED:

2024-04-25

SPECIES:

AUTHORS:

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

TITLE:

Germline AGO2 mutations impair RNA interference and human neurological development.

JOURNAL:

Nature communications Nov 2020, Vol 11, pp. 5797

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. PUBMED: 33199684
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