RT Journal Article
T1 Autism-like phenotype and risk gene mRNA deadenylation by CPEB4 mis-splicing.
A1 Parras, Alberto
A1 Anta, Hector
A1 Santos-Galindo, Maria
A1 Swarup, Vivek
A1 Elorza, Ainara
A1 Nieto-Gonzalez, Jose L
A1 Pico, Sara
A1 Hernandez, Ivo H
A1 Diaz-Hernandez, Juan I
A1 Belloc, Eulalia
A1 Rodolosse, Annie
A1 Parikshak, Neelroop N
A1 Peñagarikano, Olga
A1 Fernandez-Chacon, Rafael
A1 Irimia, Manuel
A1 Navarro, Pilar
A1 Geschwind, Daniel H
A1 Mendez, Raul
A1 Lucas, Jose J
K1 Autism spectrum disorders
K1 Translation
AB Common genetic contributions to autism spectrum disorder (ASD) reside in risk gene variants that individually have minimal effect sizes. As environmental factors that perturb neurodevelopment also underlie idiopathic ASD, it is crucial to identify altered regulators that can orchestrate multiple ASD risk genes during neurodevelopment. Cytoplasmic polyadenylation element binding proteins 1-4 (CPEB1-4) regulate the translation of specific mRNAs by modulating their poly(A)-tails and thereby participate in embryonic development and synaptic plasticity. Here we find that CPEB4 binds transcripts of most high-confidence ASD risk genes. The brains of individuals with idiopathic ASD show imbalances in CPEB4 transcript isoforms that result from decreased inclusion of a neuron-specific microexon. In addition, 9% of the transcriptome shows reduced poly(A)-tail length. Notably, this percentage is much higher for high-confidence ASD risk genes, correlating with reduced expression of the protein products of ASD risk genes. An equivalent imbalance in CPEB4 transcript isoforms in mice mimics the changes in mRNA polyadenylation and protein expression of ASD risk genes and induces ASD-like neuroanatomical, electrophysiological and behavioural phenotypes. Together, these data identify CPEB4 as a regulator of ASD risk genes.
PB Nature Publishing Group
YR 2018
FD 2018-08-15
LK http://hdl.handle.net/10668/12840
UL http://hdl.handle.net/10668/12840
LA en
NO Parras A, Anta H, Santos-Galindo M, Swarup V, Elorza A, Nieto-González JL, et al. Autism-like phenotype and risk gene mRNA deadenylation by CPEB4 mis-splicing. Nature. 2018 Aug;560(7719):441-446. doi: 10.1038/s41586-018-0423-5.
DS RISalud
RD Jul 29, 2025