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Old-fashioned Karyotyping Points to GRIK4 in Psychiatric Disorders

2 August 2006. Sure, you might need a $250,000 sequencer to do genetics these days, but sometimes a well-trained pair of eyes is all you need to spot a genetic anomaly. A study published July 4 in the early online Molecular Psychiatry by Ben Pickard and colleagues at the University of Edinburgh in Scotland describes evidence that disruption of the GRIK4 (KA1) glutamate receptor gene underlies a case of schizophrenia. They also provide association data linking the gene to both schizophrenia and bipolar disorder (see SRF live discussion on common etiology of psychotic disorders).

But it all begins with an experienced cytologist, like author Pat Malloy, simply lining up some chromosomes in the microscope and spotting one that doesn’t look quite right. Staining will reveal bands of high and low gene density that characterize individual chromosomes. To most of us, it might seem like trying to identify individual zebras by their stripes, but to the well-trained eye, the bands not only identify the chromosomes, they also reveal deletions of entire regions or movement of a region from one chromosome to another (translocations). (For those of us who are genetics-challenged, much fun and some knowledge about these processes can be had at the University of Utah’s Genetic Science Learning Center. Don’t miss the Make a Karyotype game.)

The study of such rare chromosomal abnormalities is a specialty of the Edinburgh group led by David Porteous, and in this case, Pickard, Walter Muir, and colleagues found that a patient with mild learning disability (mental retardation) and schizophrenia has disruptions involving chromosomes 2, 8, and 11. The breakpoints disrupt a number of genes; however, the researchers found the GRIK4 gene the most promising candidate for involvement in the patient’s clinical picture. The breakpoint on chromosome 11 lies between exons 2 and 3 of the GRIK4 gene, a break that is predicted to lead to an inactive gene product. GRIK4 is a member of the ionotropic glutamate receptor family (specifically in the kainate responsive group—less well-known than the NMDA and AMPA glutamate receptors). Two other disrupted genes found in this region of chromosome 11 but not investigated in this study were PKNOX2/PREP2, which codes for a transcription factor, and RP26/CERKL, coding for a gene that may be involved in retinitis pigmentosa.

Beyond the large body of data implicating glutamate dysfunction in schizophrenia (see SRF Current Hypothesis paper by Moghaddam), the authors note that GRIK4 lies in a chromosomal region with some evidence for linkage to the disorder. It is also preferentially expressed in areas of the brain that are of particular relevance to schizophrenia, such as amygdala, hippocampus, and entorhinal cortex. In a case control study of karyotypically normal subjects (368 schizophrenia, 368 bipolar, and 458 normal subjects), employing 27 SNP markers, Pickard and colleagues found three SNPs and a haplotype associated with schizophrenia risk and two SNPs and a haplotype with a protective effect for bipolar disorder. The schizophrenia-linked loci were in the N-terminal (extracellular) coding region, whereas the bipolar-linked loci were in the C-terminal (cytoplasmic) coding region.

“In this patient, we believe that haploinsufficiency of this gene is most likely responsible for the psychiatric component of the patient’s diagnosis although…we cannot definitively rule out other mechanisms,” the authors conclude.—Hakon Heimer.

Pickard BS, Malloy MP, Christoforou A, Thomson PA, Evans KL, Morris SW, Hampson M, Porteous DJ, Blackwood DH, Muir WJ. Cytogenetic and genetic evidence supports a role for the kainate-type glutamate receptor gene, GRIK4, in schizophrenia and bipolar disorder. Mol Psychiatry. 2006 Jul 4; [Epub ahead of print] Abstract

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