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.

Genome-wide Association Study of Postpartum Depression Identifies a Novel Susceptibility Locus at 18q12.1

“…The CDH2 protein, also known as neural cadherin, is expressed in brain, heart and other tissues, plays a role in neural development, and CDH2 genetic mutations can cause neurodevelopmental syndromic conditions characterized by intellectual disability and hypoplasia or agenesis of the corpus callosum [42,43]. Similarly, in the neuropsychiatric domain, recent evidence indicates a link between protein maturation disruptions caused by missense CDH2 mutations and attention-deficit hyperactivity disorder [44].…”

The Neurobiology of Behavior and Its Applicability for Animal Welfare: A Review

“…Dodman and colleagues [ 98 ], used genome-wide association analyses to compare genes of Doberman pincher dogs affected by canine compulsive disorder (CCD) vs. unaffected, and reported differences in a locus of chromosome 7, where the most significant single-nucleotide polymorphism was located within the neural cadherin-2 (CDH2) gene. CDH2 mediates synapsis function in dopaminergic areas such as the ventral midbrain and prefrontal cortex [ 99 ]. Interestingly, it has been reported that some Belgian malinois dogs typically show a circling behavior (one kind of obsessive-compulsive behavior) when placed in a confined space.…”

Flying under the radar: CDH2 (N-cadherin), an important hub molecule in neurodevelopmental and neurodegenerative diseases

“…This mutation results in a single amino acid change in a nonorganized loop structure between the first extracellular domain of the protein and the pro-domain. This region is indispensable for further protease modification by proteolytic enzymes such as the FURIN protease (Halperin et al, 2021). The mutant tyrosine changes the conformation of the binding site, therefore, inhibiting the maturation of the protein.…”

“…Importantly, this change was cell-type-specific, affecting the dopaminergic neurons in the VTA which project to higher cognitive areas, highlighting the importance of CDH2 function during the previously ignored midbrain development and connectivity. The reduced tyrosine hydroxylase expression and consequent dopamine level drop in the ventral midbrain and prefrontal cortex indicates a compromised reward mechanism which could explain the increased attention-seeking behavior of the affected children (Halperin et al, 2021).…”