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 RNA-binding (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.

Fig. 1.

Alignment of human and mouse sequences. The aligned reference sequence numbers or the positions in the human genome are indicated on the left, and the end position of each sequence is indicated on the right. Asterisks indicate sequence identity. Bold text indicates quaking-binding elements previously described in the mouse. Boxed regions highlight the core and half sites of the QRE consensus sequence.

Fig. 2.

Disease effects on mRNA expression of OR genes and PC1. Messenger RNA expression levels relative to the expression of reference genes (ACTB, GAPD) for schizophrenic patients are shown. The zero line indicates the average expression level for controls. Asterisk indicates significant deviation in mRNA levels between the patients and controls (P < 0.05, P < 0.01, and P < 0.001 for one, two, and three asterisks, respectively). Mean and standard errors are given.

Fig. 3.

Schizophrenic subgroup differences in expression of OR genes and PC1. Messenger RNA expression levels relative to the expression of reference genes (ACTB, GAPD) for three groups of schizophrenic patients treated with different types of neuroleptics are shown. The zero line indicates the average expression level of all 55 schizophrenic patients. Asterisk indicates significant deviation in mRNA levels between the three groups of patients (P < 0.05, P < 0.01, and P < 0.001 for one, two, and three asterisks, respectively). Mean and standard errors are given.