CHD6 (chromodomain helicase DNA binding protein 6)

CHD6 is a chromatin remodeling protein characterized to play a role in transcriptional repression of genes and viruses. It occurs in a nuclear location as a component of a larger complex which associates with RNA Pol II. Mutations in CHD6 are associated with motor coordination defects, and development of cancers following substitutions and translocations

Differential sphingosine-1-phosphate receptor-1 protein expression in the dorsolateral prefrontal cortex between schizophrenia Type 1 and Type 2

Understanding the etiology and treatment approaches in schizophrenia is challenged in part by the heterogeneity of this disorder. One encouraging progress is the growing evidence that there are subtypes of schizophrenia. Recen

Alpha-synuclein (SNCA) polymorphisms exert protective effects on memory after mild traumatic brain injury

Problems with attention and short-term learning and memory are commonly reported after mild traumatic brain injury (mTBI). Due to the known relationships between α-synuclein (SNCA), dopaminergic transmission, and neurologic deficits, we hypothesized that SNCA polymorphisms might be associated with cognitive outcome after mTBI. A cohort of 91 mTBI patients one month after injury and 86 healthy controls completed a series of cognitive tests assessing baseline intellectual function, attentional function, and memory, and was genotyped at 13 common single nucleotide polymorphisms (SNPs) in the SNCA gene. Significant differences in two memory measures (p = 0.001 and 0.002), but not baseline intellectual function or attentional function tasks, were found between the mTBI group and controls. A highly significant protective association between memory performance and SNCA promoter SNP rs1372525 was observed in the mTBI patients (p = 0.006 and 0.029 for the long and short delay conditions of the California Verbal Learning Tests, respectively), where the presence of at least one copy of the A (minor) allele was protective after mTBI. These results may help elucidate the pathophysiology of cognitive alterations after mTBI, and thus warrant further investigation

Deletion of the Chd6 exon 12 affects motor coordination

Members of the CHD protein family play key roles in gene regulation through ATP-dependent chromatin remodeling. This is facilitated by chromodomains that bind histone tails, and by the SWI2/SNF2-like ATPase/helicase domain that remodels chromatin by moving histones. Chd6 is ubiquitously expressed in both mouse and human, with the highest levels of expression in the brain. The Chd6 gene contains 37 exons, of which exons 12-19 encode the highly conserved ATPase domain. To determine the biological role of Chd6, we generated mouse lines with a deletion of exon 12. Chd6 without exon 12 is expressed at normal levels in mice, and Chd6 Exon 12 −/− mice are viable, fertile, and exhibit no obvious morphological or pathological phenotype. Chd6 Exon 12 −/− mice lack coordination as revealed by sensorimotor analysis. Further behavioral testing revealed that the coordination impairment was not due to muscle weakness or bradykinesia. Histological analysis of brain morphology revealed no differences between Chd6 Exon 12 −/− mice and wild-type (WT) controls. The location of CHD6 on human chromosome 20q12 is overlapped by the linkage map regions of several human ataxias, including autosomal recessive infantile cerebellar ataxia (SCAR6), a nonprogressive cerebrospinal ataxia. The genomic location, expression pattern, and ataxic phenotype of Chd6 Exon 12 −/− mice indicate that mutations within CHD6 may be responsible for one of these ataxias

Immune-Related Genomic Schizophrenic Subtyping Identified in DLPFC Transcriptome.

Well-documented evidence of the physiologic, genetic, and behavioral heterogeneity of schizophrenia suggests that diagnostic subtyping may clarify the underlying pathobiology of the disorder. Recent studies have demonstrated that increased inflammation may be a prominent feature of a subset of schizophrenics. However, these findings are inconsistent, possibly due to evaluating schizophrenics as a single group. In this study, we segregated schizophrenic patients into two groups ("Type 1", "Type 2") by their gene expression in the dorsolateral prefrontal cortex and explored biological differences between the subgroups. The study included post-mortem tissue samples that were sequenced in multiple, publicly available gene datasets using different sequencing methods. To evaluate the role of inflammation, the expression of genes in multiple components of neuroinflammation were examined: complement cascade activation, glial cell activation, pro-inflammatory mediator secretion, blood-brain barrier (BBB) breakdown, chemokine production and peripheral immune cell infiltration. The Type 2 schizophrenics showed widespread abnormal gene expression across all the neuroinflammation components that was not observed in Type 1 schizophrenics. Our results demonstrate the importance of separating schizophrenic patients into their molecularly defined subgroups and provide supporting evidence for the involvement of the immune-related pathways in a schizophrenic subset

Immune-Related Genomic Schizophrenic Subtyping Identified in DLPFC Transcriptome

Well-documented evidence of the physiologic, genetic, and behavioral heterogeneity of schizophrenia suggests that diagnostic subtyping may clarify the underlying pathobiology of the disorder. Recent studies have demonstrated that increased inflammation may be a prominent feature of a subset of schizophrenics. However, these findings are inconsistent, possibly due to evaluating schizophrenics as a single group. In this study, we segregated schizophrenic patients into two groups (“Type 1”, “Type 2”) by their gene expression in the dorsolateral prefrontal cortex and explored biological differences between the subgroups. The study included post-mortem tissue samples that were sequenced in multiple, publicly available gene datasets using different sequencing methods. To evaluate the role of inflammation, the expression of genes in multiple components of neuroinflammation were examined: complement cascade activation, glial cell activation, pro-inflammatory mediator secretion, blood–brain barrier (BBB) breakdown, chemokine production and peripheral immune cell infiltration. The Type 2 schizophrenics showed widespread abnormal gene expression across all the neuroinflammation components that was not observed in Type 1 schizophrenics. Our results demonstrate the importance of separating schizophrenic patients into their molecularly defined subgroups and provide supporting evidence for the involvement of the immune-related pathways in a schizophrenic subset

DLPFC transcriptome defines two molecular subtypes of schizophrenia.

Little is known about the molecular pathogenesis of schizophrenia, possibly because of unrecognized heterogeneity in diagnosed patient populations. We analyzed gene expression data collected from the dorsolateral prefrontal cortex (DLPFC) of post-mortem frozen brains of 189 adult diagnosed schizophrenics and 206 matched controls. Transcripts from 633 genes are differentially expressed in the DLPFC of schizophrenics as compared to controls at Bonferroni-corrected significance levels. Seventeen of those genes are differentially expressed at very high significance levels (<10-8 after Bonferroni correction). The findings were closely replicated in a dataset from an entirely unrelated source. The statistical significance of this differential gene expression is being driven by about half of the schizophrenic DLPFC samples, and importantly, it is the same half of the samples that is driving the significance for almost all of the differentially expressed transcripts. Weighted gene co-expression network analysis (WGCNA) of the schizophrenic subjects, based on the transcripts differentially expressed in the schizophrenics as compared to controls, divides them into two groups. "Type 1" schizophrenics have a DLPFC transcriptome similar to that of controls with only four differentially expressed genes identified. "Type 2" schizophrenics have a DLPFC transcriptome dramatically different from that of controls, with 3529 expression array probes to 3092 genes detecting transcripts that are differentially expressed at very high significance levels. These findings were re-tested and replicated in a separate independent cohort, using the RNAseq data from the DLPFC of an independent set of schizophrenics and control subjects. We suggest the hypothesis that these striking differences in DLPFC transcriptomes, identified and replicated in two populations, imply a fundamental biologic difference between these two groups of diagnosed schizophrenics, and we propose specific paths for further testing and expanding the hypothesis

Correction: DLPFC transcriptome defines two molecular subtypes of schizophrenia.

An amendment to this paper has been published and can be accessed via a link at the top of the paper