Resequencing and Association Analysis of Six PSD-95-Related Genes as Possible Susceptibility Genes for Schizophrenia and Autism Spectrum Disorders

Abstract

PSD-95 associated PSD proteins play a critical role in regulating the density and activity of glutamate receptors. Numerous previous studies have shown an association between the genes that encode these proteins and schizophrenia (SZ) and autism spectrum disorders (ASD), which share a substantial portion of genetic risks. We sequenced the protein-encoding regions of DLG1, DLG2, DLG4, DLGAP1, DLGAP2, and SynGAP in 562 cases (370 SZ and 192 ASD patients) on the Ion PGM platform. We detected 26 rare (minor allele frequency <1%), non-synonymous mutations, and conducted silico functional analysis and pedigree analysis when possible. Three variants, G344R in DLG1, G241S in DLG4, and R604C in DLGAP2, were selected for association analysis in an independent sample set of 1315 SZ patients, 382 ASD patients, and 1793 healthy controls. Neither DLG4-G241S nor DLGAP2-R604C was detected in any samples in case or control sets, whereas one additional SZ patient was found that carried DLG1-G344R. Our results suggest that rare missense mutations in the candidate PSD genes may increase susceptibility to SZ and/or ASD. These findings may strengthen the theory that rare, non-synonymous variants confer substantial genetic risks for these disorders.

Enhanced cognition and dysregulated hippocampal synaptic physiology in mice with a heterozygous deletion of PSD‐95

“…The gene dosage‐dependent phenotypes demonstrated in our experiments may be relevant to the effects of diseases and drugs that modulate PSD‐95 levels. Very recently, rare mutations in the human DLG4 gene have been described in patients with intellectual disability and autism (Lelieveld et al ., ; Xing et al ., ). Deficient PSD‐95 expression revealed in brains of individuals with Alzheimer's disease (Gylys et al ., ; Proctor et al ., ; Savioz et al ., ), mild cognitive impairment (Sultana et al ., ; Counts et al ., ), schizophrenia (Ohnuma et al ., ; Kristiansen et al ., ; Dean et al ., ) and mood disorders (Kristiansen & Meador‐Woodruff, ; Zhao et al ., ) may underlie the synaptic dysfunction and cognitive disturbances associated with these diseases.…”

Cannabis use is associated with potentially heritable widespread changes in autism candidate gene DLGAP2 DNA methylation in sperm

“…Due to its important role in PSD signaling, even small changes in the expression of DLGAP2 can have severe consequences [26,32]. Of particular relevance, DLGAP2 has been linked to schizophrenia and importantly, has been identified as an autism candidate gene [27,28,33,34]. Differential methylation of DLGAP2 is reported in the brain of individuals with autism, and has been linked to posttraumatic stress disorder in rats [27,35].…”

Synapse and Receptor Alterations in Two Different S100B-Induced Glaucoma-Like Models

“…Gephyrin dysfunctions are further found in other neurological diseases, including stiff-man syndrome, schizophrenia, autism, epilepsy, hyperekplexia, and molybdenum cofactor deficiency [ 82 , 83 , 84 , 85 ]. Moreover, schizophrenia and autism are associated with PSD-95 gene mutations [ 86 , 87 , 88 ].…”