Genetic and Functional Analysis of the DLG4 Gene Encoding the Post-Synaptic Density Protein 95 in Schizophrenia

• Published in: PloS one Vol. 5; no. 12; p. e15107
• Main Authors: Cheng, Min-Chih, Lu, Chao-Lin, Luu, Sy-Ueng, Tsai, Ho-Min, Hsu, Shih-Hsin, Chen, Tzu-Ting, Chen, Chia-Hsiang
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.12.2010; Public Library of Science (PLoS)
• Subjects: 3' Untranslated regions; 5' Untranslated Regions; Addictions; Adult; Alleles; Analysis; Armed forces; Bioinformatics; Biology; Brain; Cellular signal transduction; Coding; Confidence intervals; Disease susceptibility; Disks Large Homolog 4 Protein; Dopamine; Exons; Female; Functional analysis; Gene expression; Gene Expression Regulation; Gene polymorphism; Gene sequencing; Genes; Genetic analysis; Genetic aspects; Genetic Predisposition to Disease; Glutamic acid receptors (ionotropic); Haplotypes; Health sciences; Hospitals; Humans; Hypotheses; Intracellular Signaling Peptides and Proteins - metabolism; Male; Markers; Medical research; Medicine; Membrane Proteins - metabolism; Mental disorders; Mental health; Middle Aged; Mutation; N-methyl-D-aspartate; N-Methyl-D-aspartic acid receptors; Neural coding; Patients; Phosphorylation; Polymorphism; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Postsynaptic density proteins; Promoter Regions, Genetic; Promoters (Genetics); Protein Structure, Tertiary; Proteins; Psychiatry; Reporter gene; Rodents; Schizophrenia; Schizophrenia - genetics; Signal transduction; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Studies; Synaptic density; Taiwan; Transduction; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0015107

Hypofunction of N-methyl-D-aspartate (NMDA) receptor-mediated signal transduction has been implicated in the pathophysiology of schizophrenia. Post-synaptic density protein 95 (PSD95) plays a critical role in regulating the trafficking and activity of the NMDA receptor and altered expression of the PSD95 has been detected in the post-mortem brain of patients with schizophrenia. The study aimed to examine whether the DLG4 gene that encodes the PSD95 may confer genetic susceptibility to schizophrenia. We re-sequenced the core promoter, all the exons, and 3' untranslated regions (UTR) of the DLG4 gene in 588 Taiwanese schizophrenic patients and conducted an association study with 539 non-psychotic subjects. We did not detect any rare mutations at the protein-coding sequences of the DLG4 gene associated with schizophrenia. Nevertheless, we identified four polymorphic markers at the core promoter and 5' UTR and one single nucleotide polymorphism (SNP) at the 3'UTR of the DLG4 gene in this sample. Genetic analysis showed an association of a haplotype (C-D) derived from 2 polymorphic markers at the core promoter (odds ratio = 1.26, 95% confidence interval = 1.06-1.51, p = 0.01), and a borderline association of the T allele of the rs13331 at 3'UTR with schizophrenia (odds ratio = 1.19, 95% confidence interval = 0.99-1.43, p = 0.06). Further reporter gene assay showed that the C-D-C-C and the T allele of the rs13331 had significant lower activity than their counter parts. Our data indicate that the expression of the DLG4 gene is subject to regulation by the polymorphic markers at the core promoter region, 5' and 3'UTR of the gene, and is associated with the susceptibility of schizophrenia.