Human QKI, a potential regulator of mRNA expression of human oligodendrocyte-related genes involved in schizophrenia

Abstract

The quaking viable mouse mutation (qk v ) is a deletion including the 5 regulatory region of the quaking gene (Qki), which causes body tremor and severe dysmyelination in mouse. The function of the human quaking gene, called quaking homolog KH domain RNAbinding (mouse) (QKI), is not well known. We have previously shown that QKI is a new candidate gene for schizophrenia. Here we show that human QKI mRNA levels can account for a high proportion (47%) of normal interindividual mRNA expression variation (and covariation) of six oligodendrocyte-related genes (PLP1, MAG, MBP, TF, SOX10, and CDKN1B) in 55 human brain autopsy samples from individuals without psychiatric diagnoses. In addition, the tightly coexpressed myelin-related genes (PLP1, MAG, and TF) have decreased mRNA levels in 55 schizophrenic patients, as compared with 55 control individuals, and most of this difference (68 -96%) can be explained by variation in the relative mRNA levels of QKI-7kb, the same QKI splice variant previously shown to be down-regulated in patients with schizophrenia. Taken together, our results suggest that QKI levels may regulate oligodendrocyte differentiation and maturation in human brain, in a similar way as in mouse. Moreover, we hypothesize that previously observed decreased activity of myelin-related genes in schizophrenia might be caused by disturbed QKI splicing.myelin ͉ quaking ͉ splice variant

The myelin-pathogenesis puzzle in schizophrenia: a literature review

“…These abnormalities in schizophrenic brains were most pronounced in the hippocampus, superior temporal and cingulate cortices. Confirmation of these gene expression abnormalities in several independent studies 102,129,132 with different brain samples and techniques provides very strong evidence for oligodendrocyte dysfunction in schizophrenia.…”

“…These findings support the notion that the altered expression of oligodendrocyte and myelin-related genes in schizophrenia is brain region-specific rather than global, which would indicate a cellular functional impairment rather than a loss of oligodendrocytes. 118,129,131 In a remarkable molecular study by Katsel et al, 132 gene expression was analyzed in multiple cortical regions as well as in the hippocampus, caudate nucleus and putamen of post-mortem schizophrenic and control brain samples. The most altered transcripts were those encoding for proteins involved in determination of glial delineation, myelin structure and adhesion proteins participating in axoglial contacts.…”

Altered expression of genes involved in ATP biosynthesis and GABAergic neurotransmission in the ventral prefrontal cortex of suicides with and without major depression

“…38 Following on a recent description of genetic association at the QKI locus, 39 two studies have gone on to document significant and widespread reductions in QKI expression (both global and transcript specific) in schizophrenia patients compared with controls and in regions overlapping with those studied here (BA44 and BA46). 40,41 This raises the intriguing possibility that a deficit in QKI common to multiple psychiatric disorders may lead to aberrant oligodendroglial development. In support of this model one microarray investigation of major depression in middle temporal gyrus (BA21) outlined reduced expression of 17 genes with roles in oligodendrocyte function.…”

Molecular dissection of NRG1-ERBB4 signaling implicates PTPRZ1 as a potential schizophrenia susceptibility gene

“…Several postmortem studies in schizophrenia have demonstrated reduced expression of oligodendrocyte-related genes, [17][18][19][20][21][67][68][69][70][71][72] some of which may be susceptibility genes for schizophrenia. 33,[72][73][74][75] Moreover, several studies have evidence for deficits in oligodendrocytes in the disorder.…”