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

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. Gitler and O. S. Birk ()
Additional contact information
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
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
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

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: 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.

Date: 2021
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-021-26426-1 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26426-1

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-021-26426-1

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().