Neuroligins (NLGNs) are a class of postsynaptic cell-adhesion molecules that interact with presynaptic Neurexins (NRXNs) and regulate synapse function. Neuroligin-4 (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 ...