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

D Halperin,R Kadir,O Wormser,O Stoler,M Drabkin,R Proskorovski-Ohayon,A Stavsky,D Gitler,Y Yogev,B Rotblat,V Dolgin,A Lotan,O S Birk,H Nudelman,Y Perez,G Meiri,T Lifschytz

doi:10.1038/s41467-021-26426-1

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.

Highlights

Attention-deficit hyperactivity disorder (ADHD) is a common childhood-onset psychiatric disorder characterized by inattention, impulsivity and hyperactivity
Whole-exome sequencing (WES), and biochemical studies, we identified a disease-associated homozygous missense mutation in CDH2, affecting proteolysis and maturation of the encoded N-cadherin adhesion protein, which is known to play a significant role in synaptogenesis, plasticityinduced long-term spine stabilization, and neurite outgrowth[4,5]
The following were excluded in all three patients: scoring below 80 on both the performance and the verbal scales of the WISC-III9, psychosis, bipolar affective disorder, Tourette syndrome, multiple chronic tics, and a first-degree relative diagnosed with bipolar affective disorder and schizophrenia

Summary

Introduction

Attention-deficit hyperactivity disorder (ADHD) is a common childhood-onset psychiatric disorder characterized by inattention, impulsivity and hyperactivity. 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. Affected individuals have difficulties in higher-level executive functions, which are mediated by latedeveloping frontal-striatal-parietal and frontal-cerebellar neuronal networks These mainly include motor and interference inhibition, working memory, sustained attention, and temporal information processing[2]. Through generation and analysis of mice homozygous for the human mutation in the mouse CDH2 ortholog, we demonstrated hyperactivity and deficient sensorimotor integration in the mutant mice and delineated downstream physiological and molecular pathways mediating the phenotype, mainly alterations in synaptic properties and defects in dopamine neurotransmission. We identify the role of CDH2 and its downstream pathways in the pathophysiology of ADHD

Methods

Results

Conclusion