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

• DOI: 10.1038/s41467-021-26426-1
• Publication Date: 2021-10-26T10:03:16Z
• Authors: D. Halperin; A. Stavsky; R. Kadir; M. Drabkin; O. Wormser; Y. Yogev; V. Dolgin; R. Proskorovski-O...; Y. Perez; H. Nudelman; O. Stoler; B. Rotblat; T. Lifschytz; A. Lotan; G. Meiri; D. Gitler; O. S. Birk
• Keywords: Neurodevelopmental disorder; Synaptogenesis

Attention-deficit hyperactivity disorder (ADHD) is a common childhood-onset psychiatric characterized by inattention, impulsivity and hyperactivity. ADHD exhibits substantial heritability, with rare monogenic variants contributing to its pathogenesis. Here we demonstrate familial caused missense mutation in CDH2, which encodes the adhesion protein N-cadherin, known play significant role synaptogenesis; affects maturation of protein. In line human phenotype, CRISPR/Cas9-mutated knock-in mice harboring mouse ortholog recapitulated core behavioral features Symptoms were modified methylphenidate, most commonly prescribed therapeutic for ADHD. The mutated exhibited impaired presynaptic vesicle clustering, attenuated evoked transmitter release decreased spontaneous release. Specific downstream molecular pathways affected both ventral midbrain prefrontal cortex, reduced tyrosine hydroxylase expression dopamine levels. We thus delineate roles CDH2-related pathophysiology