Role of the DLGAP2 Gene Encoding the SAP90/PSD-95-Associated Protein 2 in Schizophrenia

Abstract

Aberrant synaptic dysfunction is implicated in the pathogenesis of schizophrenia. The DLGAP2 gene encoding the SAP90/PSD-95-associated protein 2 (SAPAP2) located at the post-synaptic density of neuronal cells is involved in the neuronal synaptic function. This study aimed to investigate whether the DLGAP2 gene is associated with schizophrenia. We resequenced the putative promoter region and all the exons of the DLGAP2 gene in 523 patients with schizophrenia and 596 non-psychotic controls from Taiwan and conducted a case-control association analysis. We identified 19 known SNPs in this sample. Association analysis of 9 SNPs with minor allele frequency greater than 5% showed no association with schizophrenia. However, we found a haplotype (CCACCAACT) significantly associated with schizophrenia (odds ratio:2.5, p<0.001). We also detected 16 missense mutations and 1 amino acid-insertion mutation in this sample. Bioinformatic analysis showed some of these mutations were damaging or pathological to the protein function, but we did not find increased burden of these mutations in the patient group. Notably, we identified 5 private rare variants in 5 unrelated patients, respectively, including c.−69+9C>T, c.−69+13C>T, c.−69+47C>T, c.−69+55C>T at intron 1 and c.−32A>G at untranslated exon 2 of the DLGAP2 gene. These rare variants were not detected in 559 control subjects. Further reporter gene assay of these rare variants except c.−69+13C>T showed significantly elevated promoter activity than the wild type, suggesting increased DLGAP2 gene expression may contribute to the pathogenesis of schizophrenia. Our results indicate that DLGAP2 is a susceptible gene of schizophrenia.

Further Evidence for Dlgap2 as Strong Autism Spectrum Disorders/Intellectual Disability Candidate Gene

“…Chien et al [24,25] detected some common and rare genetic variants of DLGAP2 that may have implication in the pathogenesis of ASD, but they alone may not be sufficient to lead to clinical phenotypes. Li et al [18] reported rare variants in DLGAP2 associated with an increased expression of this gene in patients with SSD and Iossifov et al [26] reported a de novo missense mutation (chr8:g.1626547G>C, NM_001277161.1:c.2174G>C) affecting a conserved amino acid and predicted as deleterious in a male with ASD. Taken together, these studies and our series, suggest that the DLGAP2 gene is likely a common susceptible gene between schizophrenia and autism.…”

“…No epilepsy was noticed. Subject 7, whose phenotyping identified a moderate ID profile without assessed ASD, also presented with a de novo 22q11.21 duplication arr[hg19] 22q11.21 (18,628,540,318) …”

“…Recently, several studies have demonstrated that the DLGAP gene family is involved in the pathophysiology of various psychiatric disorders. Li et al [18] recently reported that DLGAP2 was a susceptible gene for schizophrenia and Pinto et al [13] reported DLGAP2 as a novel gene associated with ASD on the basis of a de novo 8p23.3 duplication of 817 kb intersecting DLGAP2 in a sporadic non-syndromic ASD male.…”

Genetic variability in scaffolding proteins and risk for schizophrenia and autism-spectrum disorders: a systematic review

“…Animal-model studies also appear to support an important role for DLG4 in regulating excitatory synapses and synaptic plasticity, while mutant mice also displayed clinical phenotypes related to schizophrenia and autismspectrum disorders, such as impaired learning, abnormal 49 Purcell et al 50 Iossifov et al 59 Xing et al Purcell et al 50 Iossifov et al 59 Chien et al 115 Li et al 116 Xing et al (Table 4).…”

“…For the DLG4 gene, SNPs (Table 1) and CNVs (Table 3) have been identified only in patients with schizophrenia and with 84 Zanni et al 83 Philips et al 84 Kantojärvi et al 115,116 rs2301963 (associated with decreased orbitofrontal cortex white matter volume) 117 Chien et al 115 Li et al 116 Wu et al 125 Spellmann et al 122 Zhao et al 123 De Luca et al 124 Strauss et al autism-spectrum disorders, respectively. In contrast, SNVs have been associated with both disorders (Table 2).…”