Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study tested an intervention to reduce sexual risk behaviors in a high risk impaired population: homeless African-American, Caucasian and Hispanic men with mental illness. In a comparison group clinical trial, men were assigned to an experimental cognitive-behavioral or a control intervention and followed up over 16 months. Men were recruited from a psychiatric program in two shelters for homeless men in Nashville, Tennessee. An ethnically mixed cohort of subjects (54% African-American, 42% Caucasian and 4% Hispanic) were included in the study. Most had a chronic psychiatric disorder and a co-morbid substance abuse disorder. The 257 participants who were sexually active (130 experimental, 127 control) prior to the trial were the main target of the intervention. An experimental intervention (SexG), adapted from Susser and Associates (51), comprised 6 group sessions. The control intervention was a 6-session HIV educational program. Sexual risk behavior was the primary outcome. The experimental and control groups were compared with respect to the mean score on a sexual risk index. Complete follow-up data were obtained on 257 men (100%) for the initial six-month follow-up. These individuals have been followed for the remainder of the 16-month follow-up. This intervention, (SexG), successfully reduced sexual risk behaviors of homeless mentally ill African-American, Caucasian and Hispanic men. Similar approaches may be effective in other impaired high-risk populations.
Cell Mol Biol (Noisy-le-grand) 2003 Nov
PMID:Reaching impaired populations with HIV prevention programs: a clinical trial for homeless mentally ill African-American men. 2015 66

Schizophrenia is a common psychiatric disorder with a complex genetic etiology. To understand the genetic basis of this syndrome in Portuguese Island populations, we performed a genome-wide scan of 29 families with schizophrenia, which identified a single region on 5q31-5q35 with strong linkage (NPL=3.09, P=0.0012 at D5S820). Empirical simulations set a genome-wide threshold of NPL=3.10 for significant linkage. Additional support for this locus in schizophrenia comes from higher-density mapping and mapping of 11 additional families. The combined set of 40 families had a peak NPL=3.28 (P=0.00066) at markers D5S2112-D5S820. These data and previous linkage findings from other investigators provide strong and consistent evidence for this genomic region as a susceptibility locus for schizophrenia. Exploratory analyses of a novel phenotype, psychosis, in families with schizophrenia and bipolar disorder detected evidence for linkage to the same markers as found in schizophrenia (peak NPL=3.03, P=0.0012 at D5S820), suggesting that this locus may be responsible for the psychotic symptoms observed in both diseases. Molecular Psychiatry (2004) 9, 213-218. doi:10.1038/sj.mp.4001418 Published online 30 December 2003
Mol Psychiatry 2004 Feb
PMID:Genome-wide scan in Portuguese Island families identifies 5q31-5q35 as a susceptibility locus for schizophrenia and psychosis. 1469 22

Manic-depressive (bipolar) illness is a serious psychiatric disorder with a strong genetic predisposition. The disorder is likely to be multifactorial and etiologically complex, and the causes of genetic susceptibility have been difficult to unveil. Lithium therapy is a widely used pharmacological treatment of manic-depressive illness, which both stabilizes the ongoing episodes and prevents relapses. A putative target of lithium treatment has been the inhibition of the myo-inositol monophosphatase (IMPase) enzyme, which dephosphorylates myo-inositol monophosphate in the phosphatidylinositol signaling system. Two genes encoding human IMPases have so far been isolated, namely myo-inositol monophosphatase 1 (IMPA1) on chromosome 8q21.13-21.3 and myo-inositol monophosphatase 2 (IMPA2) on chromosome 18p11.2. In the present study, we have scanned for DNA variants in the human IMPA1 and IMPA2 genes in a pilot sample of Norwegian manic-depressive patients, followed by examination of selected polymorphisms and haplotypes in a family-based bipolar sample of Palestinian Arab proband-parent trios. Intriguingly, two frequent single-nucleotide polymorphisms (-461C>T and -207T>C) in the IMPA2 promoter sequence and their corresponding haplotypes showed transmission disequilibrium in the Palestinian Arab trios. No association was found between the IMPA1 polymorphisms and bipolar disorder, neither with respect to disease susceptibility nor with variation in lithium treatment response. The association between manic-depressive illness and IMPA2 variants supports several reports on the linkage of bipolar disorder to chromosome 18p11.2, and sustains the possible role of IMPA2 as a susceptibility gene in bipolar disorder.
Mol Psychiatry 2004 Jun
PMID:Examination of IMPA1 and IMPA2 genes in manic-depressive patients: association between IMPA2 promoter polymorphisms and bipolar disorder. 1469 25

A human serotonin (5-HT)(2C) receptor gene polymorphism leads to the substitution of cysteine for serine at codon 23 (Cys23Ser); the frequency of the Ser23 allele in unrelated Caucasians is approximately 0.13. In the present study, we assessed whether Cys23Ser could affect receptor function. The two alleles were functionally compared following expression in COS-7 cells. The constitutive activity of the receptor in an in situ reconstitution system was also evaluated following expression of each allele in Sf9 cells. Using radioligands, Ser23-expressed membranes showed reduced high-affinity binding to meta-chlorophenylpiperazine (m-CPP) and 5-HT. Although the amplitude of the 5-HT-induced intracellular Ca(2+) peak did not differ between the alleles, Ser23 required higher 5-HT concentrations to elicit the same response. These differences might be due to more extensive desensitization in the Ser23 form. In the in situ reconstitution system, the 5-HT(2C) receptor displayed considerable constitutive activity, with the Ser23 allele being significantly higher in this regard than the Cys23 form. After prolonged serum deprivation in order to resensitize the receptor, four of the 15 cells expressing Ser23 showed abnormally higher m-CPP-induced sensitivity of the Ca(2+) response. These results indicate that the Ser23 allele may be constitutively more active than Cys23. Thus, Ser23 appears to be an abundant candidate allele capable of directly influencing inter-individual variation in behavior, susceptibility to mental disorder, and response to drugs including atypical antipsychotic and some antidepressant drugs that are potent 5-HT(2C) inverse agonists or antagonists.
Mol Psychiatry 2004 Jan
PMID:Modification of human 5-HT(2C) receptor function by Cys23Ser, an abundant, naturally occurring amino-acid substitution. 1469 41

Between 1997 and 2002, 48 data sets from the hippocampus were produced on samples from the Stanley Neuropathology Consortium. From these data sets, 224 total measures were available from the various subdivisions of the hippocampus. An integrative analysis of these measures was performed using a multivariate, nonparametric analysis of variance (ANOVA). ANOVA with correction for multiple comparisons indicated that parvalbumin-containing cells in CA2 were reduced in schizophrenia and bipolar disorder. In addition, reelin protein in the molecular layer of the dentate gyrus was decreased in schizophrenia, bipolar disorder, and depression at the trend level of statistical significance (P=0.065). These results strongly suggest a dysfunction of inhibitory GABA-ergic interneurons in severe mental illness. Without correction for multiple comparisons, 31 measures were abnormal in at least one disease, whereas 11 measures would be expected to appear abnormal by chance. Abnormal molecules included measures of synaptic density or neuronal plasticity (reelin, SNAP-25, BDNF, Complexin I and II), as well as parvalbumin, tyrosine receptor kinase A, glucocorticoid receptors, glutamate NR1 receptor subunits, serotonin 5HT2(A) and 5HT1(B) receptors, and dopamine D(5) receptors.
Mol Psychiatry 2004 Jun
PMID:Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the Stanley Neuropathology Consortium. 1470 30

Schizophrenia is a common mental disorder with a complex pattern of inheritance. Despite a large number of studies in the past decades, its molecular etiology remains unknown. In this study, we proposed a 'system-thinking' strategy in seeking the combined effect of susceptibility genes for a complex disorder by using paranoid schizophrenia as an example. We genotyped 85 reported single-nucleotide polymorphisms (SNPs) present in 23 genes for the dopamine (DA) metabolism pathway among 83 paranoid schizophrenics and 108 normal controls with detailed clinical and genetic information. We developed two novel multilocus approaches-the potential effective SNP combination pattern and potential effective dynamic effects analysis, by which three susceptibility genotype combinations were found to be associated with schizophrenia. These results were also validated in a family-based cohort consisting of 95 family trios of paranoid schizophrenia. The present findings suggest that the COMT and ALDH3 combination may be the most common type involved in predisposing to schizophrenia. Since the combination blocks the whole pathways for the breakdown of DA and noradrenaline, it is very likely to play a central role in developing paranoid schizophrenia.
Mol Psychiatry 2004 May
PMID:Association study of an SNP combination pattern in the dopaminergic pathway in paranoid schizophrenia: a novel strategy for complex disorders. 1511 36

Diabetic and psychiatric symptoms often appear in patients with Wolfram syndrome, and obligate carriers of WFS1 have increased prevalence of type 2 diabetes and are more likely to require hospitalization for psychiatric illness including bipolar disorder. To identify the polymorphisms in Japanese, we examined a region of approximately 50 kb covering the entire WFS1 gene, and evaluated the patterns of linkage disequilibrium. We found a total of 42 variations including 8 novel coding single nucleotide polymorphisms (A6T, A134A, N159N, T170T, E237K, R383C, V412L, and V503G), 14 novel non-coding polymorphisms, and 2 linkage disequilibrium blocks. We also performed association studies in patients with type 2 diabetes mellitus and patients with bipolar disorder. The haplotype comprising R456 and H611 was most associated with type 2 diabetes (p = 0.013) and the haplotype comprising g. -15503C/T and g. 16226G/A was most associated with bipolar disorder (p = 0.006), but neither reached significant difference after multiple adjustment. These genetic variations and linkage disequilibrium patterns in WFS1 in Japanese should be useful in further investigation of genetic diversities of WFS1 and various related disorders.
Mol Genet Metab 2004 Jul
PMID:Genetic variations in the WFS1 gene in Japanese with type 2 diabetes and bipolar disorder. 1523 38

Schizophrenia is a common, multigenic psychiatric disorder. Linkage studies, including a recent meta-analysis of genome scans, have repeatedly implicated chromosome 8p12-p23.1 in schizophrenia susceptibility. More recently, significant association with a candidate gene on 8p12, neuregulin 1 (NRG1), has been reported in several European and Chinese samples. We investigated NRG1 for association in schizophrenia patients of Portuguese descent to determine whether this gene is a risk factor in this population. We tested NRG1 markers and haplotypes for association in 111 parent-proband trios, 321 unrelated cases, and 242 control individuals. Associations were found with a haplotype that overlaps the risk haplotype originally reported in the Icelandic population ("Hap(ICE)"), and two haplotypes located in the 3' end of NRG1 (all P<0.05). However, association was not detected with Hap(ICE) itself. Comparison of NRG1 transcript expression in peripheral leukocytes from schizophrenia patients and unaffected siblings identified 3.8-fold higher levels of the SMDF variant in patients (P=0.039). Significant positive correlations (P<0.001) were found between SMDF and HRG-beta 2 expression and between HRG-gamma and ndf43 expression, suggesting common transcriptional regulation of NRG1 variants. In summary, our results suggest that haplotypes across NRG1 and multiple NRG1 variants are involved in schizophrenia.
Mol Psychiatry 2005 Apr
PMID:Support for involvement of neuregulin 1 in schizophrenia pathophysiology. 1554 78

Trauma survivors show marked differences in the severity and persistence of post-traumatic stress disorder (PTSD) symptoms. Early symptoms subside in most, but persist as acute and chronic PTSD in a significant minority. The underlying molecular mechanisms or outcome predictors determining these differences are not known. Molecular markers for identifying any mental disorder are currently lacking. Gene expression profiling during the triggering and development of PTSD may be informative of its onset and course. We used oligonucleotide microarrays to measure peripheral blood mononuclear cell (PBMC) gene expression of trauma survivors at the emergency room and 4 months later. Gene expression signatures at both time points distinguished survivors who met DSM-IV diagnostic criteria for PTSD at 1 and 4 months, from those who met no PTSD criterion. Expression signatures at both time points correlated with the severity of each of the three PTSD symptom clusters assessed 4 months following exposure among all survivors. Results demonstrate a general reduction in PBMCs' expression of transcription activators among psychologically affected trauma survivors. Several differentiating genes were previously described as having a role in stress response. These findings provide initial evidence that peripheral gene expression signatures following trauma identify an evolving neuropsychiatric disorder and are informative of its key clinical features and outcome. Replications in larger samples, as well as studies focusing on specific markers within the signatures discovered, are warranted to confirm and extend the diagnostic utility and pathogenetic implications of our results.
Mol Psychiatry 2005 May
PMID:Peripheral blood mononuclear cell gene expression profiles identify emergent post-traumatic stress disorder among trauma survivors. 1590 2

Disrupted in schizophrenia 1 (DISC1) has been identified as a putative risk factor for schizophrenia and affective disorders through study of a Scottish family with a balanced (1;11) (q42.1;q14.3) translocation, which results in the disruption of the DISC1 locus and cosegregates with major psychiatric disease. Several other reports of genetic linkage and association between DISC1 and schizophrenia in a range of patient populations have added credibility to the DISC1-schizophrenia theory, but the function of the DISC1 protein is still poorly understood. Recent studies have suggested that DISC1 plays a role in neuronal outgrowth, possibly through reported interactions with the molecules Nudel and FEZ1. Here we have analyzed the DISC1 protein sequence to identify previously unknown regions that are important for the correct targeting of the protein and conducted imaging studies to identify DISC1 subcellular location. We have identified a central coiled-coil region and show it is critical for the subcellular targeting of DISC1. This domain is independent from the C-terminal Nudel binding domain highlighting the multidomain nature/functionality of the DISC1 protein. Furthermore, we have been able to provide the first direct evidence that DISC1 is localized to mitochondria in cultured cortical neurons that are dependent on an intact cytoskeleton. Surprisingly, Nudel is seen to differentially associate with mitochondrial markers in comparison to DISC1. Disruption of the cytoskeleton results in colocalization of Nudel and mitochondrial markers-the first observation of such a direct relationship. Mitochondrial dysfunction has been implicated to play a role in schizophrenia so we speculate that mutations in DISC1 or Nudel may impair mitochondrial transport or function, initiating a cascade of events culminating in psychiatric illness.
Mol Cell Neurosci 2005 Apr
PMID:Subcellular targeting of DISC1 is dependent on a domain independent from the Nudel binding site. 1579 9


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