Relevance to Autism

Four de novo likely gene-disruptive (LGD) variants in the DLG4 gene were identified in ASD probands (three from the SPARK cohort, one from the ITAN cohort) in Wang et al., 2020. DLG4 knockout mice displayed increased repetitive behaviors, abnormal communication and social behaviors, impaired motor coordination, and increased stress reactivity and anxiety-related responses (Feyder et al., 2010). In the same report, significant association was observed between variations in two human DLG4 SNPs and reduced intraparietal sulcus volume and abnormal cortico-amygdala coupling in a normal population. DLG4 was identified in Stessman et al., 2017 as a gene reaching de novo significance for loss-of-function variants in NDD cases (FDR-corrected de novo P-value of 3.77E-03).

Molecular Function

This gene encodes a member of the membrane-associated guanylate kinase (MAGUK) family. It heteromultimerizes with another MAGUK protein, DLG2, and is recruited into NMDA receptor and potassium channel clusters. These two MAGUK proteins may interact at postsynaptic sites to form a multimeric scaffold for the clustering of receptors, ion channels, and associated signaling proteins.

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Model Summary

Characterization of functional null mutation of PSD-95 for behavioral, dendritic, and molecular phenotypic abnormalities relevant to neurodevelopmental disorders.

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