A meta-analysis of the association of the HOPA12bp polymorphism and schizophrenia

Philibert, Robert A.

doi:10.1097/01.ypg.0000194443.81813.f0

Cited by 16 publications

(12 citation statements)

References 14 publications

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“…Mutations in the human MED12 gene result in X-linked mental retardation disorders, including Opitz-Karreggia syndrome and Lujan syndrome, and these mutations are also associated with schizophrenia [13]–[15], [59], [60]. Some overlapping clinical manifestations of these syndromes, including agenesis of the corpus callosum, behavioral disturbances and cognitive deficits, are reminiscent of FASD [15], [27], [28].…”

Section: Discussionmentioning

confidence: 99%

Novel Oxytocin Gene Expression in the Hindbrain Is Induced by Alcohol Exposure: Transgenic Zebrafish Enable Visualization of Sensitive Neurons

et al. 2013

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BackgroundFetal Alcohol Spectrum Disorders (FASD) are a collection of disorders resulting from fetal ethanol exposure, which causes a wide range of physical, neurological and behavioral deficits including heightened susceptibility for alcoholism and addictive disorders. While a number of mechanisms have been proposed for how ethanol exposure disrupts brain development, with selective groups of neurons undergoing reduced proliferation, dysfunction and death, the induction of a new neurotransmitter phenotype by ethanol exposure has not yet been reported.Principal FindingsThe effects of embryonic and larval ethanol exposure on brain development were visually monitored using transgenic zebrafish expressing cell-specific green fluorescent protein (GFP) marker genes. Specific subsets of GFP-expressing neurons were highly sensitive to ethanol exposure, but only during defined developmental windows. In the med12 mutant, which affects the Mediator co-activator complex component Med12, exposure to lower concentrations of ethanol was sufficient to reduce GFP expression in transgenic embryos. In transgenic embryos and larva containing GFP driven by an oxytocin-like (oxtl) promoter, ethanol exposure dramatically up-regulated GFP expression in a small group of hindbrain neurons, while having no effect on expression in the neuroendocrine preoptic area.ConclusionsAlcohol exposure during limited embryonic periods impedes the development of specific, identifiable groups of neurons, and the med12 mutation sensitizes these neurons to the deleterious effects of ethanol. In contrast, ethanol exposure induces oxtl expression in the hindbrain, a finding with profound implications for understanding alcoholism and other addictive disorders.

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Section: Discussionmentioning

confidence: 99%

Novel Oxytocin Gene Expression in the Hindbrain Is Induced by Alcohol Exposure: Transgenic Zebrafish Enable Visualization of Sensitive Neurons

et al. 2013

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“…In 1998, we reported the discovery of the MED12 12bp (HOPA 12bp ) variant, which is a four amino acid insertional polymorphism in the portion of the gene (Opa domain) responsible for mediating Wnt pathway signaling. Over the past several years, we and others have shown that this relatively uncommon (1 in 60 X chromosomes in European populations) balanced polymorphism is a mild risk (∼1.5-fold) for a syndrome of positive symptom psychosis [9,10]. In addition, we have identified other allelic variants (e.g., HOPA 15bp ) in the same gene domain that are associated with risk for illness.…”

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confidence: 88%

Therapeutic potential of targeting gene variants in schizophrenia

Philibert¹,

Gershenfeld²

2007

Expert Review of Neurotherapeutics

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'…the search for a common final pathway for schizophrenia is seductive, but may represent a misguided frame for studying the etiology.' Robert A Philibert † and Howard K Gershenfeld † Author for correspondence University of Iowa, Department of Psychiatry & Neuroscience, Room 2-126 MEB, Iowa City, IA, 52242-1000, USA Tel.: +1 319 353 4986 Fax: +1 319 353 3003 robert-philibert@uiowa.edu Expert Rev. Neurotherapeutics 7(7), 757-760 (2007) Schizophrenia is a debilitating, chronic syndrome affecting 1% of the population worldwide with compelling medical, economic and ethical reasons for improving existing treatments. Unfortunately, despite intensive efforts by the pharmaceutical industry, the current drug discovery effort for developing improved treatments for schizophrenia via a 'one drug fits all' blockbuster approach has stalled. Although the exact reasons are complex, the numerous scientific obstacles include diagnostic uncertainties, limitations of preclinical models in nonverbal animals, lack of knowledge about etiology and the complexity of this illness (reviewed in [1]).In particular, the heterogeneity of schizophrenia presents a major challenge with many etiologic routes leading to the same complex end point, a phenomenon shared with the broad syndromes of headaches, epilepsy or cancer. Schizophrenia is one label for many separate disease processes; a lesson we have come to appreciate recently for nonfamilial sporadic autism [2], which may present with similar phenotypes caused by the deletions of many different genes. Still, the search for a common final pathway for schizophrenia is seductive, but may represent a misguided frame for studying the etiology. Nonetheless, important family studies have defined the risk to first-degree relatives of patients with schizophrenia as 8-10-times the risk in the general population. Longitudinal epidemiologic studies have convincingly shown multiple environmental risk factors for schizophrenia such as time of birth (winter or urban), in utero infections, malnutrition, obstetric complications and paternal age as 1.2-5-fold risk factors. From numerous genetic studies over the last decade and the first whole genome association studies, the genetic architecture of schizophrenia and complex traits in general appears to consist of numerous small magnitude genes as risk factors individually conferring a 1.1-1.5 odds ratio [3][4][5] and updated via the schizophrenia gene website [101]. Given this reality, drug development approaches may profit from accepting that there are a multitude of pathways to psychosis, and should create personalized approaches for some of these pathways. We envision patients will benefit from a combination or cocktail of drugs similar to those now used in refractory cases of other complex disorders such as cancer, diabetes and hypertension.How can genetics contribute to this process? In general, the identification of genetic variants influencing schizophrenia can make contributions to four distinct domains: Philibert & Gershenfeld 758Expert R...

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“…Isolation and characterization of human genomic clones bearing large trinucleotide repeats revealed a gene encoding a carboxyl terminal OPA (opposite paired) domain, which was named human OPA-containing gene (HOPA), and later renamed MED12 following its identification as a bona fide Mediator subunit [65, 77]. Initial polymorphism analysis of MED12 identified a 12 bp insertion (HOPA 12bp ) coding for four additional amino acid residues (QQHQ) in its OPA domain that subsequent association and transmission disequilibrium analyses revealed is associated with a modest risk (~1.5) for an endophenotype of schizophrenia [78, 79]. Further analyses revealed a second, rare deletion polymorphism within the MED12 OPA domain (HOPA −15bp ) that appears also to be associated with psychosis [79, 80].…”

Section: Mediator and Disorders Of Developmentmentioning

confidence: 99%

Mediator and human disease

Spaeth

Kim

Boyer

2011

Seminars in Cell & Developmental Biology

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Since the identification of a metazoan counterpart to yeast Mediator nearly 15 years ago, a convergent body of biochemical and molecular genetic studies have confirmed their structural and functional relationship as an integrative hub through which regulatory information conveyed by signal activated transcription factors is transduced to RNA polymerase II. Nonetheless, metazoan Mediator complexes have been shaped during evolution by substantive diversification and expansion in both the number and sequence of their constituent subunits, with important implications for the development of multicellular organisms. The appearance of unique interaction surfaces within metazoan Mediator complexes for transcription factors of diverse species-specific origins extended the role of Mediator to include an essential function in coupling developmentally coded signals with precise gene expression output sufficient to specify cell fate and function. The biological significance of Mediator in human development, suggested by genetic studies in lower metazoans, is emphatically illustrated by an expanding list of human pathologies linked to genetic variation or aberrant expression of its individual subunits. Here, we review our current body of knowledge concerning associations between individual Mediator subunits and specific pathological disorders. When established, molecular etiologies underlying genotype-phenotype correlations are addressed, and we anticipate that future progress in this critical area will help identify therapeutic targets across a range of human pathologies.

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A meta-analysis of the association of the HOPA12bp polymorphism and schizophrenia

Cited by 16 publications

References 14 publications

Novel Oxytocin Gene Expression in the Hindbrain Is Induced by Alcohol Exposure: Transgenic Zebrafish Enable Visualization of Sensitive Neurons

Novel Oxytocin Gene Expression in the Hindbrain Is Induced by Alcohol Exposure: Transgenic Zebrafish Enable Visualization of Sensitive Neurons

Therapeutic potential of targeting gene variants in schizophrenia

Mediator and human disease

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