A novel NLGN1 variant in ASD and its mouse model

Abstract

Autism spectrum disorder (ASD) has a strong genetic basis. About 1000 genes have been estimated to be involved in ASD, and many of these genes determine the function of synapses. In this study, we identified a novel mutation in NLGN1 gene from ASD siblings by whole-exome sequencing. To uncover its functional significance, we conducted comprehensive analysis both in vitro and in vivo. At the in vitro level, the mutant NLGN1 showed decreased expression and abnormal sub-localization in COS7 cells overexpressing NLGN1, and the induction of dendritic spines was decreased in the primary hippocampal neurons overexpressing NLGN1. The similar phenotypes were confirmed in other NLGN1 mutations identified in ASD patients and it reinforces the significant association between NLGN1 haploinsufficiency and ASD. To address how this mutation affects in vivo phenotypes, we generated knock-in mice with a Nlgn1 mutation by CRISPR/Cas9. Similar to in vitro results, Nlgn1 mutation knock-in mice exhibited a decreased level of NLGN1 in the forebrain. In a series of behavior tests, we found several autistic traits, such as abnormal social behavior and impaired spatial memory. These results suggest that this novel NLGN1 mutation involved in ASD traits and emphasize the significant association between rare mutations in NLGN1 and neuropsychiatric disorders.