Movatterモバイル変換

[0]ホーム
URL:

Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
Thehttps:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

NIH NLM Logo
Log inShow account info
Access keysNCBI HomepageMyNCBI HomepageMain ContentMain Navigation
pubmed logo
Advanced Clipboard
User Guide

Full text links

Atypon full text link Atypon Free PMC article
Full text links

Actions

.2008 Sep 30;105(39):14940-5.
doi: 10.1073/pnas.0800643105. Epub 2008 Sep 29.

A common variant in the 3'UTR of the GRIK4 glutamate receptor gene affects transcript abundance and protects against bipolar disorder

Affiliations

A common variant in the 3'UTR of the GRIK4 glutamate receptor gene affects transcript abundance and protects against bipolar disorder

B S Pickard et al. Proc Natl Acad Sci U S A..

Abstract

Underactivity of the glutamatergic system is an attractive model for the pathophysiology of several major mental illnesses. We previously described a chromosome abnormality disrupting the kainate class ionotropic glutamate receptor gene, GRIK4/KA1, in an individual with schizophrenia and learning disability (mental retardation). We also demonstrated in a case-control study that two physically separated haplotypes within this gene were significantly associated with increased risk of schizophrenia and decreased risk of bipolar disorder, respectively. The latter protective haplotype was located at the 3' end of the gene. We now report the identification from carriers of the protective haplotype of a deletion variant within the 3' untranslated region of the gene. The deletion allele also was found to be negatively associated with bipolar disorder in both initial (P = 0.00000019) and replication (P = 0.0107) case-control studies. Expression studies indicated that deletion-carrying mRNA transcripts were relatively more abundant. We postulate that this may be a direct consequence of the differences in the RNA secondary structures predicted for the insertion and deletion alleles. These data suggest a mechanism whereby the genetic protective effect is mediated through increased kainate receptor expression.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Alignment of human (INS and DEL variants), chimp, macaque, and mouse DNA sequences surrounding theGRIK4 3′UTR indel. (A) The base sequence identical to human is indicated by the gray background. The 14-bp deletion in humans is labeled, as is the STOP codon at the end of the coding sequence. (B) Corrected annotation for the deletion. It can be seen that the combination of the deletion rs6144536 (third line) and SNP rs5016722 (fourth line), followed by realignment (underlined sequence in fifth line), is equivalent to the single deletion annotation, ss79314275 (top line).
Fig. 2.
Fig. 2.
Relative expression levels of the deletion and insertionGRIK4 alleles as determined by fluorescent-labeled PCR. (A) Representative examples from the PCR assay. The FAM-labeled insertion and deletion PCR products are shown next to a 400-bp size marker. (B) Proportions of the insertion and deletion forms in SHSY-5Y genomic DNA (n = 3), cDNA samples from SHSY-5Y (two separate RT primers;n = 6), pretransfection insertion/deletion expression plasmid mix (assay replicated three times), cDNA from HEK293 cells transfected with the insertion/deletion expression plasmid mix (two separate RT primers;n = 5), and cDNA from heterozygote control human hippocampus (three samples) and cortex (five samples). Error bars indicate the standard error of the mean.
Fig. 3.
Fig. 3.
RNA secondary structure predictions of the INS- and DEL-containingGRIK4 sequences show clear differences. Dot plots for the RNA secondary structures of the sequences shown in part in Fig. 1A. The dot plots show predicted base pairings for the sequences. The bottom-left diagonal of each dot plot shows only the most conserved base pairings. The upper-right diagonal shows predicted base pairings inconsistent with all sequences in the alignment. The saturation of the dots is correlated inversely with the number of inconsistencies (saturated for no inconsistencies). The colors of the dots correspond to the frequency of types of base pairings present, to highlight compensatory mutations (red, 1; ochre, 2; green, 3; turquoise, 4; blue, 5; violet, 6). The axes of the dot plots correspond to the consensus secondary structure predictions. (A) Dot plot for the INS-containing sequences from human and chimp. (B) Dot plot for the DEL-containing sequences (human, chimp, rhesus, mouse). (C) As in (B), but with the more divergent mouse sequences removed. Two additional visualizations of these data are shown directly beneath each dot plot. (D–F) Consensus secondary sequence and structure predictions, corresponding to the lower-left diagonal of the dot plots above. The INS sequence is colored red, and the position of the DEL is highlighted with a red arrow. Conserved base pairings between (E) and (F) are shown in the blue-dashed boxes. (G–I) Mountain plots for the consensus structure predictions, corresponding to the upper right diagonal of the dot plots above.
See this image and copyright information in PMC

References

    1. Belsham B. Glutamate and its role in psychiatric illness. Hum Psychopharmacol. 2001;16:139–146. - PubMed
    1. Farber NB. The NMDA receptor hypofunction model of psychosis. Ann N Y Acad Sci. 2003;1003:119–130. - PubMed
    1. Harrison PJ, Law AJ, Eastwood SL. Glutamate receptors and transporters in the hippocampus in schizophrenia. Ann N Y Acad Sci. 2003;1003:94–101. - PubMed
    1. McCullumsmith RE, Clinton SM, Meador-Woodruff JH. Schizophrenia as a disorder of neuroplasticity. Int Rev Neurobiol. 2004;59:19–45. - PubMed
    1. Moghaddam B. Bringing order to the glutamate chaos in schizophrenia. Neuron. 2003;40:881–884. - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full text links
Atypon full text link Atypon Free PMC article
Cite
Send To

NCBI Literature Resources

MeSHPMCBookshelfDisclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

[8]ページ先頭
©2009-2026 Movatter.jp