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.
Attention-deficit hyperactivity disorder (ADHD) is one of the most common childhood-onset neuropsychiatric conditions, characterized by a persistent pattern of inattention, impulsivity, and hyperactivity, with complications often continuing into adulthood1. Affected individuals have difficulties in higher-level executive functions, which are mediated by late-developing frontal-striatal-parietal and frontal-cerebellar neuronal networks. These mainly include motor and interference inhibition, working memory, sustained attention, and temporal information processing2. Although its etiology is not well defined, ADHD appears to have substantial heritability, and as such, it has been the focus of considerable genetic research, with growing evidence that rare monogenic variants may possess an essential role in its pathogenesis3.
Here we describe three siblings of a consanguineous kindred presenting with severe ADHD, apparent as of early childhood. Through linkage analysis, 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, plasticity-induced long-term spine stabilization, and neurite outgrowth4,5. Notably, CDH2 has an essential role in regulating the proliferation of dopaminergic progenitors within the limbic system, primarily the ventral midbrain and prefrontal cortex6. Through generation and analysis of mice homozygous for the human mutation in the mouse CDH2ortholog, 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. Thus, we identify the role of CDH2 and its downstream pathways in the pathophysiology of ADHD.