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

doi:10.1073/pnas.0601213103

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

Departments of *Evolution, Genomics and Systematics, and
^§Development and Genetics, Uppsala University, SE-75236 Uppsala, Sweden; and
^¶AstraZeneca R&D, SE-15181 Södertälje, Sweden

Communicated by Tomas Hökfelt, Karolinska Institutet, Stockholm, Sweden, February 14, 2006
↵ ^†K.Å. and P.S. contributed equally to this work. (received for review September 9, 2005)

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.

Footnotes

^‖To whom correspondence should be addressed. E-mail: elena.jazin{at}ebc.uu.se
↵ ^‡Present address: Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA 15217.
Author contributions: K.Å., P.S., and E.J. designed research; K.Å. and P.S. performed research; E.J. contributed new reagents/analytic tools; K.Å., P.S., N.J., and E.J. analyzed data; and K.Å., P.S., N.J., and E.J. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations:

Abbreviations:

QRE,

Qki response element;

OR,

oligodendrocyte related;

PC1,

principal component 1;

QASE,

quaking alternative splicing element;

MBP,

myelin basic protein;

TF,

transferrin.