ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2021
An Autism-Associated Mutation Impairs Neuroligin-4 Glycosylation and Enhances Excitatory Synaptic Transmission in Human Neurons.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers, 1 of them a synthesis that pooled it.
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Who cites it
31 citing papers in PubMed, 1 synthesis or guideline pooled it, 45 citations in OpenAlex.
- Bridging Genetic Insights with Neuroimaging in Autism Spectrum Disorder-A Systematic Review.International journal of molecular sciences · 2024Pooled it
- Transcriptome profiling of neurexin- and neuroligin-deficient Caenorhabditis elegans reveals pathways underlying developmental and behavioral dysfunction.Research square · 2026Article
- <p>Harnessing MSC‑derived exosomes to modulate the pathophysiology of ASD: Recent advances and therapeutic implications (Review)</p>.International journal of molecular medicine · 2026Review
- Presynaptic Trafficking of Glutamate Decarboxylase Isoforms Is Dispensable for Basal GABAergic Neurotransmission.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2026Article
- Does Altered Membrane Glycosylation Contribute to Neurodevelopmental Dysfunction in Autism Spectrum Disorder?Membranes · 2026Review
- Autism Spectrum Disorder: The Cerebellum, Genes, and Pathways.Neurology international · 2025Review
- Linking autism risk genes to morphological and pharmaceutical screening by high-content imaging: Future directions and opinion.Psychiatry and clinical neurosciences · 2025Review
- The association between NLGN4 gene variants and the incidence of autism spectrum disorders in Guilan, Iran.IBRO neuroscience reports · 2025Article
- Glycosylation Pathways Targeted by Deregulated miRNAs in Autism Spectrum Disorder.International journal of molecular sciences · 2025Article
- Review
- Clinical glycoproteomics: methods and diseases.MedComm · 2024Review
- Decoding the genetic landscape of autism: A comprehensive review.World journal of clinical pediatrics · 2024Article
- Lowered GnT-I Activity Decreases Complex-Type N-Glycan Amounts and Results in an Aberrant Primary Motor Neuron Structure in the Spinal Cord.Journal of developmental biology · 2024Article
- Analyses of the autism-associated neuroligin-3 R451C mutation in human neurons reveal a gain-of-function synaptic mechanism.Molecular psychiatry · 2024Article
- Characterization of a Human Neuronal Culture System for the Study of Cofilin-Actin Rod Pathology.Biomedicines · 2023Article
- Defects in early synaptic formation and neuronal function in Prader-Willi syndrome.Scientific reports · 2023Article
- Glycosylation and behavioral symptoms in neurological disorders.Translational psychiatry · 2023Review
- Cortical neuronal hyperexcitability and synaptic changes in SGCE mutation-positive myoclonus dystonia.Brain : a journal of neurology · 2023Article
- Impaired OTUD7A-dependent Ankyrin regulation mediates neuronal dysfunction in mouse and human models of the 15q13.3 microdeletion syndrome.Molecular psychiatry · 2023Article
- Increased Network Inhibition in the Dentate Gyrus of Adult Neuroligin-4 Knock-Out Mice.eNeuro · 2023Article
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Authors and funding
6 authors at 3 institutions in 2 countries.
Funding
Abstract
Neuroligins (NLGNs) are a class of postsynaptic cell adhesion molecules that interact with presynaptic neurexins (NRXNs) and regulate synapse function. NLGN4 is a member of the NLGN family and consists of a unique amino acid sequence in humans that is not evolutionarily well conserved in rodents. The human-specific NLGN4 gene has been reported to be mutated in many patients with autism and other neurodevelopmental disorders. However, it remained unclear how these mutations might alter the molecular properties of NLGN4 and affect synaptic transmission in human neurons. Here, we describe a severely autistic male patient carrying a single amino acid substitution (R101Q) in the NLGN4 gene. When expressed in HEK293 cells, the R101Q mutation in NLGN4 did not affect its binding affinity for NRXNs or its capacity to form homodimers. This mutation, however, impaired the maturation of NLGN4 protein by inhibiting N-linked glycosylation at an adjacent residue (N102), which is conserved in all NLGNs. As a result, the R101Q substitution significantly decreased the surface trafficking of NLGN4 and increased its retention in the endoplasmic reticulum and Golgi apparatus. In human neurons derived from male stem cell lines, the R101Q mutation also similarly reduced the synaptic localization of NLGN4, resulting in a loss-of-function phenotype. This mutation-induced trafficking defect substantially diminished the ability of NLGN4 to form excitatory synapses and modulate their functional properties. Viewed together, our findings suggest that the R101Q mutation is pathogenic for NLGN4 and can lead to synaptic dysfunction in autism.
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