Mutation screening of the 3q29 microdeletion syndrome candidate genes DLG1 and PAK2 in schizophrenia

Abstract

Deletion of chromosome 3q29, which is associated with mental retardation and autism, was recently identified as being present in excess or occurring de novo in schizophrenia cases, being present in approximately 1/1,000 cases and 1/40,000 unscreened controls. Of the ∼20 genes in the commonly deleted region two are prominent candidates for involvement in the behavioral features of the microdeletion syndrome: DLG1 and PAK2. We report the result of mutation screening of the entire protein coding sequence of both genes in a sample of 234 unrelated cases and 272 unrelated controls from the UK. We find no evidence for any amino acid changing genetic variants in PAK2. We observe several rare and singleton non-synonymous genetic variations at DLG1, however there is no excess of these variants in cases when compared to controls. Our sample was underpowered to detect very rare or low-penetrance disease relevant alleles in the studied genes. Therefore very rare, low-to-moderate penetrance protein coding mutations or non-coding mutations at DLG1 and/or PAK2, or a nearby gene, may reproduce the behavioral characteristics of the 3q29 microdeletion.

Population-Specific Haplotype Association of the Postsynaptic Density Gene DLG4 with Schizophrenia, in Family-Based Association Studies

“…Although numerous studies have shown expression level changes and genetic association between other PSD genes and schizophrenia [42]–[48], our study failed to detect association between DLG1 , PICK1 and MDM2, and schizophrenia in Japanese cohorts, which is in line with reports for DLG1 [49] and PICK1 [50].…”

Novel treatment strategies for schizophrenia from improved understanding of genetic risk

“…Rare DLG1 mutations have been found in patients (11) along with microdeletions that include the DLG1 (16,17) (Table 1) or DLG2 (18) gene. This supports the overall concept of glutamate synapse/signalling dysfunction in schizophrenia, and drugs targeted at facilitating NMDA-R function have so far proved mildly promising (S12).…”

The genetic variability and commonality of neurodevelopmental disease

“…Despite this complication, small CNVs represent a promising avenue for future studies with sufficiently powered study populations (both in sample size and resolution) and parental cases for determining de novo status. Specific examples of small CNVs are beginning to arise in genome-wide studies, such as VIPR2 duplications in schizophrenia, partial TMLHE deletions in autism, a collection of significant events in ID/DD subtypes, and events overlapping with genes identified to contain de novo mutations and indels [Boone et al, 2010;Celestino-Soper et al, 2011;Cooper et al, 2011;Kirov et al, 2011;Vacic et al, 2011].…”

“…Recently, Carroll et al, [2011] identified rare mutations in one gene (DLG1) highlighting its potential involvement in the schizophrenia phenotype. The variability in expression is further supported by a case report of a child with autistic features, an elongated face, and normal IQ [Cobb et al, 2010].…”