Copy number variants in neurexin genes: phenotypes and mechanisms

Abstract

Neurexins are central to trans-synaptic cell adhesion and signaling during synapse specification and maintenance. The past two decades of human genetics research have identified structural variations in the neurexin gene family, in particular NRXN1 copy number variants (CNVs), implicated in multiple neuropsychiatric and developmental disorders. The heterogeneity and reduced penetrance of NRXN1 deletions, in addition to the pleiotropic, circuit-specific functions of NRXN1, present substantial obstacles to understanding how compromised NRXN1 function predisposes individuals to neuropsychiatric disorders. Here, we provide an updated review of NRXN1 genetics in disease, followed by recently published work using both human induced pluripotent stem cell (iPSC) derived systems and animal models to understand the mechanisms of disease pathophysiology. Finally, we suggest our outlook on how the field should progress to improve our understanding of neurexin mediated disease pathogenesis. We believe that understanding how structural genetic variants in NRXN1 contribute to disease pathophysiology requires parallel approaches in iPSC and mouse model systems, each leveraging their unique strengths - analysis of genetic interactions and background effects in iPSCs and neural circuit and behavioral analysis in mice.

Figure 1

Future research directions in understanding phenotypes and mechanisms of NRXN1 copy number variants. Understanding how NRXN1 CNVs contribute to human disease will require coordinated efforts between iPSCs, where genetic interactions can be explored and high-throughput screens performed, and murine genetic models, where these mutations can be placed in neural circuit and behavioral contexts (Small animal imaging data modified from Canella et al., bioRxiv, 2020; doi: https://doi.org/10.1101/2020.08.05.237958).