Format

Send to

Choose Destination
PLoS Genet. 2017 Aug 25;13(8):e1006940. doi: 10.1371/journal.pgen.1006940. eCollection 2017 Aug.

Functional significance of rare neuroligin 1 variants found in autism.

Author information

1
RIKEN Brain Science Institute, Wako, Saitama, Japan.
2
Graduate School of Biomedical Sciences, Hiroshima University, Minami, Hiroshima, Japan.
3
Department of Genetics, Perelman School of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.
4
Genomics and Computational Biology Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
5
Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America.

Abstract

Genetic mutations contribute to the etiology of autism spectrum disorder (ASD), a common, heterogeneous neurodevelopmental disorder characterized by impairments in social interaction, communication, and repetitive and restricted patterns of behavior. Since neuroligin3 (NLGN3), a cell adhesion molecule at the neuronal synapse, was first identified as a risk gene for ASD, several additional variants in NLGN3 and NLGN4 were found in ASD patients. Moreover, synaptopathies are now known to cause several neuropsychiatric disorders including ASD. In humans, NLGNs consist of five family members, and neuroligin1 (NLGN1) is a major component forming a complex on excitatory glutamatergic synapses. However, the significance of NLGN1 in neuropsychiatric disorders remains unknown. Here, we systematically examine five missense variants of NLGN1 that were detected in ASD patients, and show molecular and cellular alterations caused by these variants. We show that a novel NLGN1 Pro89Leu (P89L) missense variant found in two ASD siblings leads to changes in cellular localization, protein degradation, and to the impairment of spine formation. Furthermore, we generated the knock-in P89L mice, and we show that the P89L heterozygote mice display abnormal social behavior, a core feature of ASD. These results, for the first time, implicate rare variants in NLGN1 as functionally significant and support that the NLGN synaptic pathway is of importance in the etiology of neuropsychiatric disorders.

PMID:
28841651
PMCID:
PMC5571902
DOI:
10.1371/journal.pgen.1006940
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center