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

Daniel S. Halperin, Alexandra Stavsky, Rotem Kadir, Max Drabkin, Ohad Wormser, Yuval Yogev et al. · 2021 · 42 citationsRead the paper

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.

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A homozygous missense mutation in CDH2 (p.H150Y) causes non-syndromic familial ADHD in humans. (Consanguineous Bedouin pedigree)
Cdh2 H150Y knock-in mice exhibit hyperactivity, characterized by increased traveling distance, velocity, and mobility time. (Male 10-12 week old homozygous KI mice in open-field test)
The p.H150Y mutation significantly decreases the proteolytic cleavage efficacy of the N-cadherin prodomain by furin protease. (In vitro biochemical peptide cleavage assay)
Mutant neurons show smaller and more compact presynaptic vesicle clusters. (Ex-vivo hippocampal neurons at 14 DIV)
The readily releasable pool (RRP) of synaptic vesicles is significantly smaller in mutant neurons. (FM1-43 destaining in Cdh2 H150Y neurons)
Spontaneous synaptic release frequency (mEPSC) is significantly reduced in mutant neurons. (Patch-clamp recordings from CA1 pyramidal neurons in acute brain slices)

Setup: Human family (9 members); Male Cdh2 H150Y KI mice (n=18 to 30 per group); Primary hippocampal neuronal cultures.
How: The researchers used linkage analysis and whole-exome sequencing to identify a CDH2 mutation in a human family, then created a CRISPR/Cas9 knock-in mouse model. They employed biochemical peptide assays, behavioral testing (OFT, Y-maze, ASR), and electrophysiology/imaging (sypHy, patch-clamp) to analyze synaptic function.
Limitations: Social interaction results were inconclusive. · The study focused primarily on male mice. · The human sample size is limited to one family.

Summarized by Gemma 4 from the open-access full text · 13 Oct 2026. Read it