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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The susceptibility of developing most major psychiatric disorders is determined in part by contributions from risk alleles at multiple genetic loci. The central aim of this article is to highlight evidence from studies of neurodegenerative disorders suggesting that some of these alleles are shared by more than one psychiatric disorder, and to explore mechanisms that may underly these pleiotropic effects. The identification of constellations of susceptibility alleles associated with particular mental disorders will provide opportunities for new insights into the molecular and cellular pathophysiology of these disorders, and will have a major impact on psychiatric research and clinical care. This approach to reducing the variance in etiopathogenesis is also likely to be important for achieving the optimal use of available treatments (maximizing effectiveness and minimizing side effects), and for the discovery of novel medications or other interventions.
Mol Psychiatry 2000 Mar
PMID:Do susceptibility loci contribute to the expression of more than one mental disorder? A view from the genetics of Alzheimer's disease. 1082 39

Corticotropin-releasing hormone (CRH) is the principal regulator of the hypothalamic-pituitary-adrenal (HPA) axis and an activator of the sympathoadrenal (SA) and systemic sympathetic (SS) systems. Mental disorders, including major depression and, more recently, Alzheimer's disease have been associated with dysregulation of the HPA axis and the SA/SS systems. Treatment of rats or monkeys with the novel CRH receptor type 1 (CRH-R1) antagonist antalarmin inhibits the HPA and/or the SA/SS axes. This is the first study to examine the potential direct effect of antalarmin on human adrenal function. Adrenocortical and adrenomedullary cells were characterized by double-immunohistochemistry with anti-17 alpha hydroxylase (cortical cells) and anti-chromogranin A (chromaffin cells). Expression of CRH, ACTH, CRH type I and type II receptor mRNA were analyzed by reverse-transcription (RT) PCR. Human adrenal cortical and/or chromaffin cells in co-culture were incubated with CRH, antalarmin, and both CRH and antalarmin in vitro. Exposure of these cells to corticotropin or vehicle medium served as positive and negative controls, respectively. Cortical and chromaffin tissues were interwoven in the human adrenals, and both in situ and in the co-culture system the endocrine cell types were in close cellular contact. ACTH, CRH, and CRH-R1 and CRH-R2 mRNAs were expressed in the human adrenal as determined by RT-PCR. CRH (10-8 M) led to a moderate increase of cortisol release (145.7 +/- 20.0%) from cortical and chromaffin adrenal cells in co-culture. This effect corresponded to 41.8% of the maximal increase induced by ACTH (10-8 M). The action of CRH was completely inhibited by antalarmin. CRH, ACTH, and both CRH-R1 and CRH-R2 mRNAs are expressed in the adult human adrenal gland. CRH stimulates cortisol production in cortical and chromaffin cell co-cultures. This effect is blocked by antalarmin, a selective CRH-R1 receptor antagonist, suggesting that CRH-R1 receptors are involved in an intraadrenal CRH/ACTH control system in humans.
Mol Psychiatry 2000 Mar
PMID:Effects of a novel corticotropin-releasing-hormone receptor type I antagonist on human adrenal function. 1082 40

Linkage studies have suggested a locus for bipolar disorder as well as schizophrenia in the pericentric region of chromosome 18. Several candidate genes have been identified in the region including ACTH, IMP, and G(olf), however no reports of mutations in families showing linkage to the 18p11 locus have been reported. Recently, mild linkage disequilibrium has been observed with a polymorphic marker that maps within the G(olf) gene and schizophrenia in families from Germany and Israel, suggesting that a gene mapping near G(olf) may be involved in psychiatric disorders. A BAC and cosmid contig around the G(olf) locus has been generated and BAC clones were used for cDNA selection experiments. Several novel genes have been identified which are expressed in the brain. These genes may be possible candidate genes for psychiatric illness.
Mol Psychiatry 2000 Jul
PMID:Identification of candidate genes for psychiatric disorders on 18p11. 1088 49

Medical treatment with various cytokines can provoke psychiatric symptoms. Conversely, psychiatric patients can display abnormalities in cytokine and neurotrophic factor expression. Such observations have pointed to the potential contribution of cytokines and growth factors to schizophrenic pathology and/or etiology. The cellular targets of the relevant factors and the nature of their actions remain to be explored in mental illness, however. Recent physiological studies demonstrate that cytokines and neurotrophic factors can markedly influence synaptic transmission and plasticity upon acute or chronic application. Moreover, many of the molecular alterations observed in the schizophrenic brain are consistent with abnormalities in cytokine and neurotrophic factor regulation of these molecules. In this review, we summarize these molecular pathology findings for schizophrenia and highlight the neurodevelopmental activities of cytokines and neurotrophic factors that may contribute to the etiology or pathology of this illness.
Mol Psychiatry 2000 Nov
PMID:Cytokine and growth factor involvement in schizophrenia--support for the developmental model. 1112 90

Accumulation of neurobiological knowledge points to neurodevelopmental origins for certain psychotic and mood disorders. Recent landmark postmortem reports implicate Reelin, a secretory glycoprotein responsible for normal lamination of brain, in the pathology of schizophrenia and bipolar disorders. We employed quantitative immunocytochemistry to measure levels of Reelin protein in various compartments of hippocampal formation in subjects diagnosed with schizophrenia, bipolar disorder and major depression compared to normal controls. Significant reductions were observed in Reelin-positive adjusted cell densities in the dentate molecular layer (ANOVA, P < 0.001), CA4 area (ANOVA, P < 0.001), total hippocampal area (ANOVA, P < 0.038) and in Reelin-positive cell counts in CA4 (ANOVA, P < 0.042) of schizophrenics vs controls. Adjusted Reelin-positive cell densities were also reduced in CA4 areas of subjects with bipolar disorder (ANOVA, P < 0.001) and nonsignificantly in those with major depression. CA4 areas were also significantly reduced in schizophrenic (ANOVA, P < 0.009) patients. No significant effects of confounding variables were found. The exception was that family history of psychiatric illness correlated strongly with Reelin reductions in several areas of hippocampus (CA4, adjusted cell density, F = 13.77, P = 0.001). We present new immunocytochemical evidence showing reductions in Reelin expression in hippocampus of subjects with schizophrenia, bipolar disorder and major depression and confirm recent reports documenting a similar deficit involving Reelin expression in brains of subjects with schizophrenia and bipolar disorder.
Mol Psychiatry 2000 Nov
PMID:Reduction in Reelin immunoreactivity in hippocampus of subjects with schizophrenia, bipolar disorder and major depression. 1112 96

Bipolar affective disorder is a genetically complex psychiatric disorder with a population prevalence of approximately 1%. We have previously reported cosegregation of bipolar affective disorder and Darier's disease, a dominant skin disorder with a neuropsychiatric component. The gene for Darier's disease was mapped to chromosome 12q23-q24.1 and linkage studies by us and others have subsequently implicated this region as harbouring a susceptibility gene for bipolar affective disorder. In this study we have investigated the Darier's disease gene ATP2A2, the calcium pumping ATPase SERCA2, as a potential susceptibility gene for bipolar disorder under the hypothesis that variations in SERCA2 have pleiotropic effects in brain. Support for this hypothesis comes from clinical evidence of neuropsychiatric abnormalities in Darier's disease, genetic data produced in our study showing non-random clustering of missense mutations in ATP2A2 in neuropsychiatric Darier patients, and functional data demonstrating the role of SERCA2 in intracellular calcium regulation. In a panel of 15 unrelated bipolar patients from multiply affected families showing increased allele sharing at markers in the 12q23-q24.1 region, we performed mutational screening of the ATP2A2 coding sequence, promoter regions, and 3' untranslated region and identified six sequence variations. These were analysed in a large sample of bipolar patients (n = 324) and control subjects (n = 327). Analysis of allele and genotype distributions for all six variations, and of haplotype frequencies showed no evidence for the involvement of ATP2A2 in producing susceptibility to bipolar disorder.
Mol Psychiatry 2001 Jan
PMID:Exclusion of the Darier's disease gene, ATP2A2, as a common susceptibility gene for bipolar disorder. 1124 92

Depression is the most prevalent functional psychiatric disorder in late life. The problem of motor disorders associated with antidepressant use is relevant in the elderly. Elderly people are physically more frail and more likely to be suffering from physical illness, and any drug given may exacerbate pre-existing diseases, or interact with other drug treatments being administered for physical conditions. Antidepressants have been reported to induce extrapyramidal symptoms, including parkinsonism. These observations prompted us to review the neurobiological mechanism that may be involved in this complex interplay including neurotransmitters and neuronal circuits involved in movement and emotion control and their changes related to aging and disease. The study of the correlations between motor and mood disorders and their putative biochemical bases, as presented in this review, provide a rationale either to understand or to foresee motor side effects for psychotropic drugs, in particular antidepressants.
Mol Psychiatry 2001 Mar
PMID:Extrapyramidal symptoms and antidepressant drugs: neuropharmacological aspects of a frequent interaction in the elderly. 1131 14

Two overlapping and antiparallel genes on chromosome 1, Disrupted In Schizophrenia 1 and 2 (DISC1 and DISC2), are disrupted by a (1;11)(q42.1;q14.3) translocation which segregates with schizophrenia through at least four generations of a large Scottish family. Consequently, these genes are worthy of further investigation as candidate genes potentially involved in the aetiology of major psychiatric illness. We have constructed a contiguous clone map of PACs and cosmids extending across at least 400 kb of the chromosome 1 translocation breakpoint region and this has provided the basis for examination of the genomic structure of DISC1. The gene consists of thirteen exons, estimated to extend across at least 300 kb of DNA. The antisense gene DISC2 overlaps with exon 9. Exon 11 contains an alternative splice site that removes 66 nucleotides from the open reading frame. The final intron of DISC1 belongs to the rare AT-AC class of introns. We have also mapped marker DIS251 in close proximity to DISC1, localising the gene within a critical region identified by several independent studies. Information regarding the structure of the DISC1 gene will facilitate assessment of its involvement in the aetiology of major mental illness in psychotic individuals unrelated to carriers of the translocation.
Mol Psychiatry 2001 Mar
PMID:Genomic structure and localisation within a linkage hotspot of Disrupted In Schizophrenia 1, a gene disrupted by a translocation segregating with schizophrenia. 1131 19

The 102-T/C polymorphism of the 5-HT(2A) receptor gene was analysed in 159 patients with major depression and 164 unrelated and healthy controls using a case-control design. Allele and genotype frequencies did not differ between cases and controls. No differences according to sex, age of onset, melancholia, suicidal behaviour or family history of psychiatric illness were found. However, genotype distributions significantly differed between patients with seasonal pattern in their episodes (MDS) and patients with no seasonal pattern (N-MDS) (chi(2) = 10.63; P = 0.004). A seasonal pattern was 7.57 times more frequent in 102C-allele carriers than in 102T homozygous (95.1% of patients MDS carried 102C-allele vs 72% of patients N-MDS (chi(2) = 9.45, df=1, P = 0.002; OR = 7.57 (95% CI: 1.65--48.08)). These results suggest that variation in the 5-HT2A receptor gene may play a role in the development of major depression with seasonal pattern and support the existence of a genetic and etiological heterogeneity underlying the diagnosis of major depression.
Mol Psychiatry 2001 Mar
PMID:Variability in the 5-HT(2A) receptor gene is associated with seasonal pattern in major depression. 1131 30

Anorexia nervosa (AN) is a common, severe and disabling psychiatric disorder, characterized by profound weight loss and body image disturbance. Family and twin studies indicate a significant genetic contribution and pharmacological data suggest possible dysfunction of the serotonergic and dopaminergic pathways. Catechol-O-methyltransferase (COMT) is a candidate gene for mediating susceptibility to AN since it is involved in the dopamine catabolism and because its functional polymorphism (Val/Met 158) determines high (H) and low (L) enzymatic activity alleles. Fifty-one Israeli AN patients and their parents were genotyped with the COMT polymorphism. Using the haplotype relative risk (HRR) method it was found that the frequency of the H allele among alleles transmitted to AN patients from their parents was significantly higher than in those not transmitted (68% vs 51% chi(2) = 5.20, df = 1, P = 0.023, odds ratio: 2.01). Transmission disequilibrium test (TDT) revealed that out of 49 heterozygote parents the H allele was transmitted to AN patients 33 times while the L allele was transmitted only 16 (McNemar's chi(2) = 5.90, df = 1, P = 0.015). Our study suggests that the COMT gene is associated with genetic susceptibility to AN, and that individuals homozygous for the high activity allele (HH) have a two-fold increased risk for development of the disorder.
Mol Psychiatry 2001 Mar
PMID:Association of anorexia nervosa with the high activity allele of the COMT gene: a family-based study in Israeli patients. 1131 31


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