Language
English
Publication Date
10-1-2026
Journal
PLoS Genetics
DOI
10.1371/journal.pgen.1012341
PMID
42886765
PMCID
PMC13705613
PubMedCentral® Posted Date
10-16-2026
PubMedCentral® Full Text Version
Post-print
Abstract
Neuroligin-3 (NLGN3) was first identified as a X-linked risk gene associated with autism spectrum disorder (ASD). Most reported variants are identified in males who inherited their variants from an unaffected mother, but de novo variants have also been identified in both affected heterozygous females and hemizygous males. The p.R451C variant was the initial variant associating NLGN3 with ASD and has been heavily investigated, yet little is known about the functional consequences of other NLGN3 variants. To determine the functional consequences of other NLGN3 variants in vivo, we generated transgenic Drosophila models corresponding to a de novo variant (p.R175W) identified in a heterozygous female proband with ASD, a maternally inherited variant (p.R451C) identified in a hemizygous male with ASD, and another maternally inherited variant identified in a male (p.R597W) associated with sleep disorder and ASD. In Drosophila, loss of the fly homolog, Nlg3, altered sleep patterns, synaptic architecture, and vesicle dynamics, which were rescued by the expression of the human NLGN3Ref allele. When comparing the variants, the p.R175W variant and the maternally inherited p.R451C variant altered synapse morphology with minimal effects on vesicle dynamics, and the p.R597W variant altered sleep and vesicle dynamics with minimal impact on synapse morphology. Using overexpression models, human NLGN3Ref altered sleep patterns and synaptic morphology. Moreover, the p.R175W variant exacerbated sleep phenotypes, and the p.R175W and p.R451C variants exacerbated synapse morphology phenotypes. Together, our findings suggest that the de novo NLGN3 p.R175W variant identified in a heterozygous female exhibits gain-of-function properties, while maternally inherited variants have context-dependent functional impact. Moreover, some NLGN3 variants disrupt synaptic development, while other variants alter synaptic function, suggesting that NLGN3 variants have differential effects. These functional differences may provide insight into the heterogeneity of individuals with ASD.
Keywords
Animals, Male, Neuroligins, Synapses, Female, Humans, Sleep, Cell Adhesion Molecules, Neuronal, Animals, Genetically Modified, Autism Spectrum Disorder, Drosophila melanogaster, Drosophila Proteins, Disease Models, Animal, Drosophila, Membrane Proteins, Nerve Tissue Proteins
Published Open-Access
yes
Recommended Citation
Townsley, Rebekah E; Andrews, Jonathan C; Srivastav, Saurabh; et al., "NLGN3 Autism Variants Have Distinct Functional Impact on Synapses and Sleep Behavior in Drosophila" (2026). Faculty, Staff and Students Publications. 8371.
https://digitalcommons.library.tmc.edu/baylor_docs/8371