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CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice

Author

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  • D. Halperin

    (The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Faculty of Health Sciences, Ben-Gurion University of the Negev)

  • A. Stavsky

    (Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev)

  • R. Kadir

    (The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Faculty of Health Sciences, Ben-Gurion University of the Negev)

  • M. Drabkin

    (The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Faculty of Health Sciences, Ben-Gurion University of the Negev)

  • O. Wormser

    (The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Faculty of Health Sciences, Ben-Gurion University of the Negev)

  • Y. Yogev

    (The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Faculty of Health Sciences, Ben-Gurion University of the Negev)

  • V. Dolgin

    (The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Faculty of Health Sciences, Ben-Gurion University of the Negev)

  • R. Proskorovski-Ohayon

    (The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Faculty of Health Sciences, Ben-Gurion University of the Negev)

  • Y. Perez

    (The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Faculty of Health Sciences, Ben-Gurion University of the Negev
    Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California
    University of California)

  • H. Nudelman

    (Ben-Gurion University of the Negev)

  • O. Stoler

    (Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev)

  • B. Rotblat

    (Ben-Gurion University of the Negev)

  • T. Lifschytz

    (Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center)

  • A. Lotan

    (Biological Psychiatry Laboratory, Hadassah-Hebrew University Medical Center)

  • G. Meiri

    (Pre-School Psychiatry Unit, Soroka University Medical Center
    Faculty of Health Sciences, Ben-Gurion University of the Negev)

  • D. Gitler

    (Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev)

  • O. S. Birk

    (The Morris Kahn Laboratory of Human Genetics, National Institute for Biotechnology in the Negev and Faculty of Health Sciences, Ben-Gurion University of the Negev
    Genetics Institute, Soroka University Medical Center)

Abstract

Attention-deficit hyperactivity disorder (ADHD) is a common childhood-onset psychiatric disorder characterized by inattention, impulsivity and hyperactivity. ADHD exhibits substantial heritability, with rare monogenic variants contributing to its pathogenesis. Here we demonstrate familial ADHD caused by a missense mutation in CDH2, which encodes the adhesion protein N-cadherin, known to play a significant role in synaptogenesis; the mutation affects maturation of the protein. In line with the human phenotype, CRISPR/Cas9-mutated knock-in mice harboring the human mutation in the mouse ortholog recapitulated core behavioral features of hyperactivity. Symptoms were modified by methylphenidate, the most commonly prescribed therapeutic for ADHD. The mutated mice exhibited impaired presynaptic vesicle clustering, attenuated evoked transmitter release and decreased spontaneous release. Specific downstream molecular pathways were affected in both the ventral midbrain and prefrontal cortex, with reduced tyrosine hydroxylase expression and dopamine levels. We thus delineate roles for CDH2-related pathways in the pathophysiology of ADHD.

Suggested Citation

  • D. Halperin & A. Stavsky & R. Kadir & M. Drabkin & O. Wormser & Y. Yogev & V. Dolgin & R. Proskorovski-Ohayon & Y. Perez & H. Nudelman & O. Stoler & B. Rotblat & T. Lifschytz & A. Lotan & G. Meiri & D, 2021. "CDH2 mutation affecting N-cadherin function causes attention-deficit hyperactivity disorder in humans and mice," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26426-1
    DOI: 10.1038/s41467-021-26426-1
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    References listed on IDEAS

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    1. Julia Brasch & Kerry M. Goodman & Alex J. Noble & Micah Rapp & Seetha Mannepalli & Fabiana Bahna & Venkata P. Dandey & Tristan Bepler & Bonnie Berger & Tom Maniatis & Clinton S. Potter & Bridget Carra, 2019. "Visualization of clustered protocadherin neuronal self-recognition complexes," Nature, Nature, vol. 569(7755), pages 280-283, May.
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