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Autism-like phenotype and risk gene mRNA deadenylation by CPEB4 mis-splicing

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  • Alberto Parras

    (Centro de Biología Molecular ‘Severo Ochoa’ (CBMSO) CSIC/UAM
    Instituto de Salud Carlos III)

  • Héctor Anta

    (Hospital del Mar Medical Research Institute (IMIM)
    Barcelona Institute of Science and Technology)

  • María Santos-Galindo

    (Centro de Biología Molecular ‘Severo Ochoa’ (CBMSO) CSIC/UAM
    Instituto de Salud Carlos III)

  • Vivek Swarup

    (Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, UCLA)

  • Ainara Elorza

    (Centro de Biología Molecular ‘Severo Ochoa’ (CBMSO) CSIC/UAM
    Instituto de Salud Carlos III)

  • José L. Nieto-González

    (Instituto de Salud Carlos III
    Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla and Departamento de Fisiología Médica y Biofísica)

  • Sara Picó

    (Centro de Biología Molecular ‘Severo Ochoa’ (CBMSO) CSIC/UAM
    Instituto de Salud Carlos III)

  • Ivó H. Hernández

    (Centro de Biología Molecular ‘Severo Ochoa’ (CBMSO) CSIC/UAM
    Instituto de Salud Carlos III
    Universidad Autónoma de Madrid)

  • Juan I. Díaz-Hernández

    (Centro de Biología Molecular ‘Severo Ochoa’ (CBMSO) CSIC/UAM
    Instituto de Salud Carlos III)

  • Eulàlia Belloc

    (Barcelona Institute of Science and Technology)

  • Annie Rodolosse

    (Barcelona Institute of Science and Technology)

  • Neelroop N. Parikshak

    (Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, UCLA)

  • Olga Peñagarikano

    (Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, UCLA
    School of Medicine, University of the Basque Country (UPV/EHU)
    Centro de Investigación Biomédica en Red en Salud Mental (CIBERSAM))

  • Rafael Fernández-Chacón

    (Instituto de Salud Carlos III
    Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla and Departamento de Fisiología Médica y Biofísica)

  • Manuel Irimia

    (Barcelona Institute for Science and Technology
    Universitat Pompeu Fabra)

  • Pilar Navarro

    (Hospital del Mar Medical Research Institute (IMIM))

  • Daniel H. Geschwind

    (Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, UCLA)

  • Raúl Méndez

    (Barcelona Institute of Science and Technology
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

  • José J. Lucas

    (Centro de Biología Molecular ‘Severo Ochoa’ (CBMSO) CSIC/UAM
    Instituto de Salud Carlos III)

Abstract

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.

Suggested Citation

  • Alberto Parras & Héctor Anta & María Santos-Galindo & Vivek Swarup & Ainara Elorza & José L. Nieto-González & Sara Picó & Ivó H. Hernández & Juan I. Díaz-Hernández & Eulàlia Belloc & Annie Rodolosse &, 2018. "Autism-like phenotype and risk gene mRNA deadenylation by CPEB4 mis-splicing," Nature, Nature, vol. 560(7719), pages 441-446, August.
  • Handle: RePEc:nat:nature:v:560:y:2018:i:7719:d:10.1038_s41586-018-0423-5
    DOI: 10.1038/s41586-018-0423-5
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    Cited by:

    1. Ningyuan You & Chang Liu & Yuxin Gu & Rong Wang & Hanying Jia & Tianyun Zhang & Song Jiang & Jinsong Shi & Ming Chen & Min-Xin Guan & Siqi Sun & Shanshan Pei & Zhihong Liu & Ning Shen, 2024. "SpliceTransformer predicts tissue-specific splicing linked to human diseases," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Kyung Ah Han & Taek-Han Yoon & Jinhu Kim & Jusung Lee & Ju Yeon Lee & Gyubin Jang & Ji Won Um & Jong Kyoung Kim & Jaewon Ko, 2024. "Specification of neural circuit architecture shaped by context-dependent patterned LAR-RPTP microexons," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

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