This web page was produced as an assignment for Genetics 677, an undergraduate course at UW-Madison.
GRIK2 & Bipolar Disease (BPD)
Bipolar disorder, also known as manic-depressive disorder, is a brain disorder that causes unusual shifts in an individual's mood, energy, and ability to function. These shifts are extreme, and can result in damaged relationships, poor performance, and too frequently can end in suicide. There are treatments for this disorder that allow people with this disease to experience relief, but the greatest challenge lies in early and accurate diagnosis of this serious mental disorder.(1)
Many famous people have been diagnosed, or thought to have battled with the disease, including Robert Downey Jr., Britney Spears, Ben Stiller, Mozart, Beethoven, Vincent Van Gogh, Winston Churchill, Abraham Lincoln, Edgar Allen Poe, and possibly Charles Darwin.
Figure 1: An artist's rendition of the duality that characterizes the manic states of bipolar disorder.
Recent meta-analyses of linkage studies detected either no significant genome-wide findings or, using a different methodology, only two genome-wide significant peaks, on chromosome 6q and on 8q21.
Genome-wide association studies have also not brought a consistent focus - each has identified new loci, while none of the previously identified loci were replicated.
Twin studies have been limited by relatively small sample sizes but have indicated a substantial genetic contribution, as well as environmental influence.
The overall heritability of the bipolar spectrum has been put at 0.71.
Diverse findings point strongly to heterogeneity, with different genes being implicated in different families.
Advanced parental age has been linked to a somewhat increased chance of bipolar disorder in offspring, consistent with a hypothesis of increased new genetic mutations.
It is also suggested that individual genes are likely to have only a small effect and to be involved in some aspect related to the disorder (and a broad range of "normal" human behavior) rather than the disorder per se. (5)
There are many genes currently being researched that are candidates for contributing roles towards the development of bipolar disorder in humans. GRIK2, a kainate receptor, is one of the most promising. Kainate receptors are non-NMDA ionotropic receptors which respond to the neurotransmitter glutamate. They are involved in excitatory neurotransmission by activating postsynaptic receptors, and in inhibitor neurotransmission by modulating release of the inhibitory neurotransmitter GABA through a presynaptic mechanism.(3)There are five types of kainate receptor subunits, GluR5, GluR6, GluR7, KA1, and KA2, which can all be rearranged to form a tetramer. (3) GluR6 is the subunit of GRIK2 that is thought to be linked to the development of many psychiatric disorders, including bipolar disorder. Presumably the mutation impairs the ligand binding site of the molecule. (2)
One primary literature study investigated expression of glutamate receptors, including that of GRIK2 and its associated subunit Glur6. Glutamate receptors mediate the majority of excitatory neurotransmission in the brain. Because neuropathological states and possibly human disorders, including BPD, may involve kainate glutamate receptors, the authors isolated a cDNA clone for the human GluR6 subunit of the GRIK2 receptor. This clone shows a very high sequence similarity with that of the rat, except for a part of the 3' untranslated region in which there is a TAA triplet repeat. This is supported by my Homologene and Blast evidence in this webpage. In addition, when the protein was overexpressed in human embryonic kidney 293 cells, it had a molecular weight, an antibody recognition, and a glutamate ligand-binding profile similar to those of the rat GluR6 receptor. Northern analysis showed expression in both human cerebral and cerebellar cortices. These are areas of the brain responsible for mood regulation, which makes sense given the pathology of BPD. By PCR analysis of rodent-human monochromosomal cell lines, the human GluR6 could be assigned to chromosome 6. This study and others that will certainly follow should provide the basis for expression or linkage studies of the GluR6 kainate receptor in human neurological disease, such as BPD. (4)
Figure 2: The 3D structure of the GRIK2 molecule. Arrows indicate GluR6 mutation sites.
About 5.7 million American adults or about 2.6% of the American population over the age of 18 have bipolar disorder. It is likely that many more have the disease and go undiagnosed for all, or much of their lives. Due to lack of education and awareness in much of the world, it is not known how many people may be afflicted worldwide.
In addition, bipolar disorder can develop at all stages of life, further complicating accurate and early diagnosis. Once developed, however, the disorder is a long-term illness that must always be carefully managed, and the therapies most effective can vary throughout an individual's lifetime. (3)
Figure 3: A visual representation of the spectrum between manic and depressive episodes.
This site's goal is an in-depth, genomic, and bioinformatic analysis of the human gene, GRIK2 and its associated subunit GluR6, in relation to its putative role in the development of bipolar disorder in humans.
References:
1. (Figure 1) Boot Camps for Teens. Image retrieved on February 3rd, 2009 from http://teenbootcamps.com/blog/
2. (Figure 2) Neurological Correlates: The Neuroscience of Dysfunctional Behavior. Image retrieved on February 3rd, 2009. http://neurologicalcorrelates.com/wordpress/
3. (Figure 3) NIMH: The National Institute of Mental Health. June 26th, 2008. http://www.nimh.nih.gov/health/publications/bipolar-disorder/introduction.shtml. Accessed on February 3rd, 2009.
4. Paschen, W., CD Blackstone, RL Huganir, and CA Ross. "Human GluR6 kainate receptor (GRIK2): molecular cloning, expression, polymorphism, and chromosomal assignment." 20 Apr. 1994. NCBI. 13 May 2009 <http://www.ncbi.nlm.nih.gov/sites/entrez>.
5. Wikipedia "Bipolar Disorder". Accessed 5/13/09.
Ashley Bateman, [email protected], last updated 5/13/09
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