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

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.

• Authors: 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, O S Birk
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 6187 (10 26 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34702855 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• Antigens, CD
• CDH2 protein, human
• Cadherins
• Methylphenidate
• Tyrosine 3-Monooxygenase
• Dopamine

Topics

• Animals
• Antigens, CD (chemistry, genetics, metabolism)
• Attention Deficit Disorder with Hyperactivity (drug therapy, genetics, metabolism, physiopathology)
• Cadherins (chemistry, genetics, metabolism)
• Child
• Dopamine (metabolism)
• Gene Expression Profiling
• Homozygote
• Humans
• Locomotion (drug effects)
• Male
• Methylphenidate (therapeutic use)
• Mice
• Mutation
• Neurons (metabolism)
• Prefrontal Cortex (metabolism)
• Protein Conformation
• Siblings
• Synaptic Transmission (drug effects)
• Synaptic Vesicles (metabolism)
• Tyrosine 3-Monooxygenase (metabolism)