Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neuregulins (NRGs) are cell-cell signaling proteins that are ligands for receptor tyrosine kinases of the ErbB family. The neuregulin family of genes has four members: NRG1, NRG2, NRG3, and NRG4. Relatively little is known about the biological functions of the NRG2, 3, and 4 proteins, and they are considered in this review only briefly. The NRG1 proteins play essential roles in the nervous system, heart, and breast. There is also evidence for involvement of NRG signaling in the development and function of several other organ systems, and in human disease, including the pathogenesis of schizophrenia and breast cancer. There are many NRG1 isoforms, raising the question "Why so many neuregulins?" Study of mice with targeted mutations ("knockout mice") has demonstrated that isoforms differing in their N-terminal region or in their epidermal growth factor (EGF)-like domain differ in their in vivo functions. These differences in function might arise because of differences in expression pattern or might reflect differences in intrinsic biological characteristics. While differences in expression pattern certainly contribute to the observed differences in in vivo functions, there are also marked differences in intrinsic characteristics that may tailor isoforms for specific signaling requirements, a theme that will be emphasized in this review.
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PMID:Neuregulins: functions, forms, and signaling strategies. 1264 63

Recent twin studies confirm that schizophrenia is highly heritable, but attempts to locate and identify genes have proved to be difficult. This is largely because major genes appear to be rare or nonexistent. Instead, genetic liability almost certainly results from the combined effects of multiple susceptibility loci and most studies have been under-equipped to detect such effects. Nevertheless, several regions of the genome have been implicated by more than one linkage study and chromosome 22q has been implicated by linkage and by studies of patients with microdeletions. Recent work attempting to refine regions of interest using linkage dysequilibrium mapping has identified four promising and novel "positional candidates;" they are neuregulin-1 on chromosome 8p-p21, G72 located at chromosome 13q34, dysbindin at 6p22.3, and proline dehydrogenase, which is a gene that maps to chromosome 22q11. In addition, there is renewed interest in a fifth gene, catechol-O-methyltransferase, also on chromosome 22q11.
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PMID:Linkage and association studies of schizophrenia. 1268 91

Although valuable antischizophrenic drugs exist, they only partially ameliorate symptoms and elicit substantial side effects. Classic neuroleptic drugs act by blocking dopamine receptors. They can relieve some symptoms but not behavioral withdrawal features that are designated "negative" symptoms. Clozapine and related newer atypical neuroleptics may be more efficacious in relieving negative symptoms. Understandng their actions may facilitate new drug discovery. Agents influencing glutamate neurotransmission and N-methyl-D-aspartate receptors, especially the cotransmitter D-serine, are promising. Stimulation of the alpha7 subtype of nicotinic acetylcholine receptor may also be efficacious. The search for genes linked to schizophrenia has revealed several leads that may permit development of novel therapeutic agents. Promising genes include disrupted-in-schizophrenia-1, dysbindin, and neuregulin.
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PMID:Schizophrenia: neural mechanisms for novel therapies. 1276 34

Genetic linkage and association have implicated neuregulin-1 (NRG-1) as a schizophrenia susceptibility gene. We measured mRNA expression levels of the three major isoforms of NRG-1 (ie type I, type II, and type III) in the postmortem dorsolateral prefrontal cortex (DLPFC) from matched patients and controls using real-time quantitative RT-PCR. Expression levels of three internal controls-GAPDH, cyclophilin, and beta-actin-were unchanged in schizophrenia, and there were no changes in the absolute levels of the NRG-1 isoforms. However, type I expression normalized by GAPDH levels was significantly increased in schizophrenia DLPFC (by 23%) and positively correlated with antipsychotic medication dosage. Type II/type I and type II/type III ratios were significantly decreased (18 and 23% respectively). There was no effect on the NRG-1 mRNA levels of genotype at two SNPs previously associated with schizophrenia, suggesting that these alleles are not functionally responsible for abnormal NRG-1 expression patterns in patients. Subtle abnormalities in the expression patterns of NRG-1 mRNA isoforms in DLPFC may be associated with schizophrenia.
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PMID:Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia. 1456 72

Two recent association studies have implicated the neuregulin-1 gene (NRG1) at chromosome 8p21-22 as a susceptibility gene for schizophrenia. Stefansson et al identified three 'at-risk' haplotypes (HapA, B and C) which spanned the NRG1 locus and shared a common core haplotype. Subsequently, they demonstrated evidence that the core haplotype was associated with schizophrenia in an independent Scottish sample. To confirm and refine this haplotype we investigated the NRG1 locus in an independent Irish case-control sample. We did not find the core haplotype to be associated in our sample. However, we identified a refined 2-marker haplotype (HapB(IRE)) that shared common alleles with one of the Icelandic 'at-risk' haplotypes and is in significant excess in the Irish cases (19.4%) vs controls (12.3%) (P=0.013). This refined 'at-risk' haplotype is also in significant excess in the Scottish case sample (17.0% vs 13.5%; P=0.036). Interestingly, this refined 'at-risk' haplotype is positioned close to an EST cluster of unknown function (Hs.97362) within intron 1 of NRG1.
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PMID:Confirmation and refinement of an 'at-risk' haplotype for schizophrenia suggests the EST cluster, Hs.97362, as a potential susceptibility gene at the Neuregulin-1 locus. 1496 80

We discuss in this review the role of the neuregulin (NRG1) gene in schizophrenia. NRG1 contributes to the genetics of schizophrenia in both Icelandic and Scottish schizophrenia patients. NRG1 participates in glutamatergic signaling by regulating the N-methyl-D-aspartate (NMDA) receptor through the interaction of the NRG1 protein and its receptors. NRG1 plays a central role in neural development and is most likely involved in regulating synaptic plasticity, or how the brain responds or adapts to the environment. The discovery that defects in NRG1 signaling may be involved in some cases of schizophrenia, not only implicates NRG1, but suggests that its biological pathway, active both at developing and mature synapses, is worth inspecting further in a search for other schizophrenia genes possibly in epistasis with NRG1.
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PMID:Neuregulin 1 and schizophrenia. 1500 Mar 48

Refractory schizophrenia has limited therapeutic options. Schizophrenia can be considered to be a disease of abnormal synaptic plasticity. Neuregulin is a member of the epithelial growth factor family, which induces growth and differentiation of epithelial, glial and muscle cells in culture. Neuregulin has been documented to be important in synaptic plasticity. The important role of neuregulin in synaptic plasticity as well as its developmental role have increasingly been documented recently. The actions of neuregulin are mediated through ERB receptors. Neuregulin can bind directly to erbB3 and erbB4 receptors and receptor heterodimerization allows neuregulin dependent activation of erbB2. The role of Erb 2 could make it possible to use the monoclonal antibody against it for improving the synaptic plasticity through the action on neuregulin. The use of trastuzumab (Her2 antibody) as targeted therapy is well documented in metastatic carcinoma of breast. Also intra-thecal administration of trastuzumab has been reported to be safe in carcinomatous meningitis. Here it is being hypothesized that intra-thecal administration of trastuzumab would improve synaptic plasticity there by making refractory schizophrenia amenable to treatment.
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PMID:Intrathecal therapy with trastuzumab may be beneficial in cases of refractory schizophrenia. 1505 Jan 3

Schizophrenia is a devastating psychiatric disease that affects 0.5-1% of the world's adult population. The hypothesis that this disease is a developmental disorder of the nervous system with late onset of its characteristic symptoms has been gaining acceptance in past years. However, the anatomical, cellular and molecular bases of schizophrenia remain unclear. Numerous studies point to alterations in different aspects of brain development as possible causes of schizophrenia, including defects in neuronal migration, neurotransmitter receptor expression and myelination. Recently, the gene that encodes neuregulin-1 (NRG1) has been identified as a potential susceptibility gene for schizophrenia, and defects in the expression of erbB3, one of the NRG1 receptors, have been shown to occur in the prefrontal cortex of schizophrenic patients, suggesting that NRG1-erbB signaling is involved in the pathogenesis of schizophrenia. These findings open new approaches to defining the molecular and cellular basis of schizophrenia in more mechanistic terms.
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PMID:Neuregulin 1-erbB signaling and the molecular/cellular basis of schizophrenia. 1516 66

The neuregulin-1 gene (NRG1) at chromosome 8p21-22 has been implicated as a schizophrenia susceptibility gene in Icelandic, Scottish, Irish and mixed UK populations. The shared ancestry between these populations led us to investigate the NRG1 polymorphisms and appropriate marker haplotypes for linkage and/or association to schizophrenia in the Irish study of high-density schizophrenia families (ISHDSF). Neither single-point nor multi-point linkage analysis of NRG1 markers gave evidence for linkage independent of our pre-existing findings telomeric on 8p. Analysis of linkage disequilibrium (LD) across the 252 kb interval encompassing the 7 marker core Icelandic/Scottish NRG1 haplotype revealed two separate regions of modest LD, comprising markers SNP8NRG255133, SNP8NRG249130 and SNP8NRG243177 (telomeric) and microsatellites 478B14-428, 420M9-1395, D8S1810 and 420M9-116I12 (centromeric). From single marker analysis by TRANSMIT and FBAT we found no evidence for association with schizophrenia for any marker. Haplotype analysis for the three SNPs in LD region 1 and, separately, the four microsatellites in LD region 2 (analyzed in overlapping 2-marker windows), showed no evidence for overtransmission of specific haplotypes to affected individuals. We therefore conclude that if NRG1 does contain susceptibility alleles for schizophrenia, they impact quite weakly on risk in the ISHDSF.
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PMID:No evidence for linkage or association of neuregulin-1 (NRG1) with disease in the Irish study of high-density schizophrenia families (ISHDSF). 1519 97

Neuregulin-1 (NRG-1) plays important roles in the development and plasticity of the brain, and it has recently been identified as a susceptibility gene for schizophrenia. Though there are rodent data, little is known about its distribution in the human brain. The aim of this study was to ascertain the localization of NRG-1 and its mRNA in multiple regions of the normal adult human brain. We investigated NRG-1 mRNA in 11 subjects using in situ hybridization and northern analysis, and NRG-1 protein in six subjects using immunohistochemistry and Western blotting. NRG-1 mRNA was present as bands of approximately 2, 3 and 6 kb. It was clearly detected in the prefrontal cortex (middle laminae), hippocampal formation (except CA1), cerebellum, oculomotor nucleus, superior colliculus, red nucleus and substantia nigra pars compacta. At the cellular level, NRG1 mRNA was abundant in hippocampal and cortical pyramidal neurons and some interneurons, and in cerebellar Purkinje cells and Golgi cells. NRG-1 protein was detected as bands of approximately 140, 110, 95 and 60 kD. Immunohistochemistry revealed NRG-1 in many cell populations, consistent with the mRNA data, being prominent in pyramidal neurons, Purkinje cells, several brainstem nuclei, and white matter neurons. Moderate NRG-1 immunoreactivity was also observed in cerebellar and dentate gyrus granule cells, and some glia. Within neurons, NRG-1 staining was primarily somatodendritic; in the cell body staining was granular, with clustering close to the plasma and nuclear membranes. There was also labeling of some fiber tracts, and local areas of neuropil (e.g. in the dentate nucleus) suggestive of a pre-synaptic location of NRG-1. The data show a widespread expression of NRG-1 in the adult human brain, including, but not limited to, brain areas and cell populations implicated in schizophrenia. Using these normative data, future studies can ascertain whether the role of NRG-1 in the disease is mediated, or accompanied, via alterations in its expression.
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PMID:Neuregulin-1 (NRG-1) mRNA and protein in the adult human brain. 1521 75


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