Neuregulin 1 Transcripts Are Differentially Expressed in Schizophrenia and Regulated by 5′ SNPs Associated With the Disease

Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford OX3 7JX, United Kingdom.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 05/2006; 103(17):6747-52. DOI: 10.1073/pnas.0602002103
Source: PubMed


Genetic variation in neuregulin 1 (NRG1) is associated with schizophrenia. The disease-associated SNPs are noncoding, and their functional implications remain unknown. We hypothesized that differential expression of the NRG1 gene explains its association to the disease. We examined four of the disease-associated SNPs that make up the original risk haplotype in the 5' upstream region of the gene for their effects on mRNA abundance of NRG1 types I-IV in human postmortem hippocampus. Diagnostic comparisons revealed a 34% increase in type I mRNA in schizophrenia and an interaction of diagnosis and genotype (SNP8NRG221132) on this transcript. Of potentially greater interest, a single SNP within the risk haplotype (SNP8NRG243177) and a 22-kb block of this core haplotype are associated with mRNA expression for the novel type IV isoform in patients and controls. Bioinformatic promoter analyses indicate that both SNPs lead to a gain/loss of putative binding sites for three transcription factors, serum response factor, myelin transcription factor-1, and High Mobility Group Box Protein-1. These data implicate variation in isoform expression as a molecular mechanism for the genetic association of NRG1 with schizophrenia.

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Available from: Cynthia Shannon Weickert
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    • "Virtually all ''at-risk'' haplotypes map to noncoding regions of the human NRG1 gene (Stefansson et al., 2002; Weickert et al., 2012), suggesting that altered NRG1 expression increases disease susceptibility . Indeed, both reduced and increased expression of distinct NRG1 variants have been observed in studies of postmortem brain tissue from schizophrenia patients (Bertram et al., 2007; Law et al., 2006). This includes elevated expression of membrane-bound ''cysteine-rich domain'' (CRD)-NRG1 (Weickert et al., 2012), the predominant NRG1 isoform in the human brain (Liu et al., 2011). "
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    ABSTRACT: j.celrep.2014.07.026 This is an open access article under the CC BY-NC-ND license ( SUMMARY Neuregulin-1 (NRG1) gene variants are associated with increased genetic risk for schizophrenia. It is unclear whether risk haplotypes cause elevated or decreased expression of NRG1 in the brains of schizophrenia patients, given that both findings have been reported from autopsy studies. To study NRG1 functions in vivo, we generated mouse mu-tants with reduced and elevated NRG1 levels and analyzed the impact on cortical functions. Loss of NRG1 from cortical projection neurons resulted in increased inhibitory neurotransmission, reduced synaptic plasticity, and hypoactivity. Neuronal over-expression of cysteine-rich domain (CRD)-NRG1, the major brain isoform, caused unbalanced ex-citatory-inhibitory neurotransmission, reduced syn-aptic plasticity, abnormal spine growth, altered steady-state levels of synaptic plasticity-related proteins, and impaired sensorimotor gating. We conclude that an ''optimal'' level of NRG1 signaling balances excitatory and inhibitory neurotransmis-sion in the cortex. Our data provide a potential path-omechanism for impaired synaptic plasticity and suggest that human NRG1 risk haplotypes exert a gain-of-function effect. INTRODUCTION
    Full-text · Article · Aug 2014 · Cell Reports
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    • "Genetic variation in NRG1 was associated to an increased risk for developing schizophrenia [6]. Among the several markers in this gene, the single-nucleotide polymorphism (SNP) rs6994992 (SNP8NRG243177) in the promoter region is particularly interesting because of its effect on the expression levels of type-IV NRG1 in human post-mortem brain samples and in luciferase in vitro assays [7,8]. Other genetic variants related to NRG1 have been associated to schizophrenia, such as the non-synonymous (Arg/Gln) SNP rs3924999 [9]. "
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    ABSTRACT: Background Neuregulins are a family of signalling proteins that orchestrate a broad range of cellular responses. Four genes encoding Neuregulins 1–4 have been identified so far in vertebrates. Among them, Neuregulin 1 and Neuregulin 3 have been reported to contribute to an increased risk for developing schizophrenia. We hypothesized that three specific variants of these genes (rs6994992 and rs3924999 for Neuregulin 1 and rs10748842 for Neuregulin 3) that have been related to this illness may modify information processing capacity in the cortex, which would be reflected in electrophysiological parameters (P3b amplitude or gamma noise power) and/or cognitive performance. Methods We obtained DNA from 31 patients with schizophrenia and 23 healthy controls and analyzed NRG1 rs6994992, NRG1 rs3924999 and NRG3 rs10748842 promoter polymorphisms by allelic discrimination with real-time polymerase chain reaction (PCR). We compared cognitive outcome, P300 amplitude parameters and an electroencephalographic measure of noise power in the gamma band between the groups dichotomized according to genotype. Results Contrary to our hypothesis, we could not detect any significant influence of variation in Neuregulin 1/Neuregulin 3 polymorphisms on cognitive performance or electrophysiological parameters of patients with schizophrenia. Conclusions Despite our findings, we cannot discard that other genetic variants and, more likely, interactions between those variants and with genetic variation related to different pathways may still influence cerebral processing in schizophrenia.
    Full-text · Article · Jun 2014 · Annals of General Psychiatry
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    • "Law and colleagues showed that p110δ is the major PI3K catalytic isoform signaling downstream of the neuregulin 1 (Nrg-1) receptor ErbB4 (Law et al., 2012; Figure 1). Both ErbB4, as well as Nrg-1 have been identified as risk genes for schizophrenia (Stefansson et al., 2002; Law et al., 2006; Norton et al., 2006; Silberberg et al., 2006). There are several isoforms of ErbB4, which have different capabilities of binding to, and activating PI3K catalytic subunits (Veikkolainen et al., 2011). "
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    ABSTRACT: The phosphoinositide 3-kinase (PI3K) complex plays important roles in virtually all cells of the body. The enzymatic activity of PI3K to phosphorylate phosphoinositides in the membrane is mediated by a group of catalytic and regulatory subunits. Among those, the class I catalytic subunits, p110α, p110β, p110γ, and p110δ, have recently drawn attention in the neuroscience field due to their specific dysregulation in diverse brain disorders. While in non-neuronal cells these catalytic subunits may have partially redundant functions, there is increasing evidence that in neurons their roles are more specialized, and confined to distinct receptor-dependent pathways. This review will summarize the emerging role of class I PI3K catalytic subunits in neurotransmitter-regulated neuronal signaling, and their dysfunction in a variety of neurological diseases, including fragile X syndrome, schizophrenia, and epilepsy. We will discuss recent literature describing the use of PI3K subunit-selective inhibitors to rescue brain disease-associated phenotypes in in vitro and animal models. These studies give rise to the exciting prospect that these drugs, originally designed for cancer treatment, may be repurposed as therapeutic drugs for brain disorders in the future.
    Full-text · Article · Feb 2014 · Frontiers in Molecular Neuroscience
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