Sunday, April 06, 2008

Myelin-- Schizophrenia and Autism Genes Concerning Myelin Formation are Mutated

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1: Neurosci Biobehav Rev. 2006;30(4):551-61. Epub 2006 Jan 30.Related Articles, Links
RNA metabolism and dysmyelination in schizophrenia.

McInnes LA, Lauriat TL.

Department of Psychiatry and Human Genetics, Mount Sinai School of Medicine, New York, NY 10029, USA.

Decreased expression of a subset of oligodendrocyte and myelin-related genes is the most consistent finding among gene expression studies of postmortem brain tissue from subjects with schizophrenia (SCZ), although heritable variants have yet to be found that can explain the bulk of this data. However, expression of the glial gene Quaking (QKI), encoding an RNA binding (RBP) essential for myelination, was recently found to be decreased in SCZ brain. Both oligodendrocyte/myelin related genes, and other RBPs that are known or predicted to be targets of QKI, are also decreased in SCZ. Two different quaking mutant mice share some pathological features in common with SCZ, including decreased expression of myelin-related genes and dysmyelination, without gross destruction of white matter. Therefore, although these mice are not a model of SCZ per se, understanding the similarities and differences in gene expression between brains from these mice and subjects with SCZ could help parse out distinct genetic pathways underlying SCZ.

: Am J Med Genet B Neuropsychiatr Genet. 2006 Jan 5;141(1):84-90.Related Articles, Links
Human QKI, a new candidate gene for schizophrenia involved in myelination.

Aberg K, Saetre P, Lindholm E, Ekholm B, Pettersson U, Adolfsson R, Jazin E.

Department of Evolution, Genomics and Systematics, Uppsala University, Norbyvägen 18D, 752-36 Uppsala, Sweden.

We have previously shown that chromosome 6q25-6q27 includes a susceptibility locus for schizophrenia in a large pedigree from northern Sweden. In this study, we fine-mapped a 10.7 Mb region, included in this locus, using 42 microsatellites or SNP markers. We found a 0.5 Mb haplotype, likely to be inherited identical by decent, within the large family that is shared among the majority of the patients (69%). A gamete competition test of this haplotype in 176 unrelated nuclear families from the same geographical area as the large family showed association to schizophrenia (empirical P-value 0.041). The only gene located in the region, the quaking homolog, KH domain RNA binding (mouse) (QKI), was investigated in human brain autopsies from 55 cases and 55 controls using a high-resolution mRNA expression analysis. Relative mRNA expression levels of two QKI splice variants were clearly downregulated in schizophrenic patients (P-value 0.0004 and 0.03, respectively). The function of QKI has not been studied in humans, but the mouse homolog is involved in neural development and myelination. In conclusion, we present evidence from three unrelated sample-sets that propose the involvement of the QKI gene in schizophrenia. The two family based studies suggest that there may be functional variants of the QKI gene that increase the susceptibility of schizophrenia in northern Sweden, whereas the case-control study suggest that splicing of the gene may be disturbed in schizophrenic patients from other geographical origins. Taken together, we propose QKI as a possible target for functional studies related to the role of myelination in schizophrenia. (c) 2005 Wiley-Liss, Inc.

Published online on April 25, 2006, 10.1073/pnas.0601213103

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Human QKI, a potential regulator of mRNA expression of human oligodendrocyte-related genes involved in schizophrenia
( myelin | quaking | splice variant )

Karolina Åberg *, Peter Saetre , Niclas Jareborg ¶, and Elena Jazin ||
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 (received for review September 9, 2005)

The quaking viable mouse mutation (qkv) 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.


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.

K.Å. and P.S. contributed equally to this work.

Present address: Department of Human Genetics, University of Pittsburgh, Pittsburgh, PA 15217.

||To whom correspondence should be addressed.

Elena Jazin, E-mail:



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