G72/G30 in Schizophrenia and Bipolar Disorder: Review and Meta-analysis

National Institute of Mental Health Intramural Research Program, National Institutes of Health, U.S. Department of Health and Human Services, Bethesda, Maryland 20892-3719, USA.
Biological Psychiatry (Impact Factor: 10.26). 08/2006; 60(2):106-14. DOI: 10.1016/j.biopsych.2006.01.019
Source: PubMed


Association of the G72/G30 locus with schizophrenia and bipolar disorder has now been reported in several studies. The G72/G30 locus may be one of several that account for the evidence of linkage that spans a broad region of chromosome 13q. However, the story of G72/G30 is complex. Our meta-analysis of published association studies shows highly significant evidence of association between nucleotide variations in the G72/G30 region and schizophrenia, along with compelling evidence of association with bipolar disorder. But the associated alleles and haplotypes are not identical across studies, and some strongly associated variants are located approximately 50 kb telomeric of G72. Interestingly, G72 and G30 are transcribed in opposite directions; hence, their transcripts could cross-regulate translation. A functional native protein and functional motifs for G72 or G30 remain to be demonstrated. The interaction of G72 with d-amino acid oxidase, itself of interest as a modulator of N-methyl-d-aspartate receptors through regulation of d-serine levels, has been reported in one study and could be a key functional link that deserves further investigation. The association findings in the G72/G30 region, among the most compelling in psychiatry, may expose an important molecular pathway involved in susceptibility to schizophrenia and bipolar disorder.

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    • "At the genetic level, people with the polymorphic variations of this gene have been determined to be susceptible to schizophrenia [2]. In addition to schizophrenia , the variations of G72 gene have also been discovered to correlate with bipolar disorder [3] [4]. The most famous single nucleotide polymorphism (SNP), rs2391191 resulting in Arg30 to Lys, has been identified as having a correlation with the decreased thickness of the brain cortex in patients with schizophrenia [5]. "
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    ABSTRACT: G72 is a schizophrenia-susceptible gene encoding a polypeptide with 153 amino acids. In 2002, it was originally proposed as an activator of D-amino acid oxidase (DAOA) that could enhance the activity of DAAO and subsequently reduce the neurotransmission of N -methyl-D-aspartate receptors. However, several controversial findings have been reported recently. Due to a number of inconsistent descriptions of pLG72’s biofunctions, this study aims to identify the cellular effects induced by pLG72 in U87 cells using systems biology approaches. The analyses of transcriptomics and biological networks showed that pLG72 might be involved in the induction of oxidative stress. To confirm the in silico prediction, we tested and discovered that overexpression of pLG72 effectively enhanced reactive oxygen species (ROS) in U87 cells and, furthermore, this induction can be quenched by Tempol, a general ROS scavenger. Therefore, G72 -transgenic mice presenting some psychiatric symptoms, along with the pLG72 level being significantly increased in the serum of patients with schizophrenia, have led us to propose that the ROS enhancement in mental diseases may be from the overexpression of pLG72 in brain cells.
    01/2015; 2015:1-7. DOI:10.1155/2015/429253
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    • "Interestingly, the NALCN gene lies within a region on chromosome 13q that has shown linkage to both BD and SCZ (reviewed in Detera-Wadleigh and McMahon, 2006). More specifically, the correlation between NALCN mRNA expression and the SCZ-associated gene GABRB2 in human brain (Kang et al., 2011), along with the association between the Drosophila homolog, na with circadian rhythms (disruptions of which are a hallmark of BD) suggest that NALCN may play a role in these two disorders (reviewed in Lenox et al., 2002). "
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    ABSTRACT: Ion channels are crucial components of cellular excitability and are involved in many neurological diseases. This review focuses on the sodium leak, G protein-coupled receptors (GPCRs)-activated NALCN channel that is predominantly expressed in neurons where it regulates the resting membrane potential and neuronal excitability. NALCN is part of a complex that includes not only GPCRs, but also UNC-79, UNC-80, NLF-1 and src family of Tyrosine kinases (SFKs). There is growing evidence that the NALCN channelosome critically regulates its ion conduction. Both in mammals and invertebrates, animal models revealed an involvement in many processes such as locomotor behaviors, sensitivity to volatile anesthetics, and respiratory rhythms. There is also evidence that alteration in this NALCN channelosome can cause a wide variety of diseases. Indeed, mutations in the NALCN gene were identified in Infantile Neuroaxonal Dystrophy (INAD) patients, as well as in patients with an Autosomal Recessive Syndrome with severe hypotonia, speech impairment, and cognitive delay. Deletions in NALCN gene were also reported in diseases such as 13q syndrome. In addition, genes encoding NALCN, NLF- 1, UNC-79, and UNC-80 proteins may be susceptibility loci for several diseases including bipolar disorder, schizophrenia, Alzheimer's disease, autism, epilepsy, alcoholism, cardiac diseases and cancer. Although the physiological role of the NALCN channelosome is poorly understood, its involvement in human diseases should foster interest for drug development in the near future. Toward this goal, we review here the current knowledge on the NALCN channelosome in physiology and diseases.
    Frontiers in Cellular Neuroscience 05/2014; 8:132. DOI:10.3389/fncel.2014.00132 · 4.29 Impact Factor
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    • "Nevertheless, lithium has been used for over 35 years for the treatment of BD, being the gold standard and perhaps the most widely used drug. Various theories on the mechanism of lithium action have been proposed, from alterations in ionic transport to modulation of gene expression [6] [7]. However, the precise neurobiological mechanisms through which lithium exerts its clinical effects are not clear, and some results found in the literature are contradictory [2]. "
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    ABSTRACT: The molecular basis of bipolar disorder (BD) is still unknown as is the mechanism through which lithium, the therapy of choice, exerts its effects in treatment of BD. So far, no biomarkers exist to facilitate diagnosis of BD or treatment evaluation. To investigate whether BD and its treatment with lithium leaves a characteristic signature in the serum proteome, we used SELDI-TOF MS to analyze individual serum samples from BD patients treated with lithium (BD-plus-Li, n=15) or other drugs (BD-minus-Li, n=10) and from healthy controls (n=15). Interestingly, features of 28 kDa (one peak) and 14 kDa (three peaks) showed a decreased level in the BD-minus-Li group and a level restored to that of the control group in the BD-plus-Li group. To reveal the identity of these features, we subjected pooled serum samples from both BD groups to the 2-D DIGE technology and identified 28 kDa apolipoprotein A-I (apo A-I) and three 14 kDa fragments thereof as upregulated in the BD-plus-Li group. Immunoturbidimetry, a routine clinical assay, verified the characteristic apo A-I signature in individual serum samples. In conclusion, we propose apo A-I as a candidate marker that can visualize response to lithium treatment at the serum protein level.
    Proteomics 01/2011; 11(2):261-9. DOI:10.1002/pmic.201000371 · 3.81 Impact Factor
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