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General Summary I Alvarado, F Sissingh and J Licinio Molecular Psychiatry (2002) 7, 665–668 2002 Nature Publishing Group All rights reserved 1359-4184/02 $25.00 www.nature.com/mp General Summary I Alvarado, F Sissingh and J Licinio UCLA, Los Angeles, CA, USA Molecular Psychiatry (2002) 7, 665–668. doi:10.1038/ teins of epidermal growth factor (EGF) and its homol- sj.mp.4001225 ogues are known to regulate development of the dopa- minergic neurons as well as dopamine metabolism, and might be involved in schizophrenic pathology and/or etiology. To test this possibility, levels of these SCIENTIFIC CORRESPONDENCE proteins and their receptors were determined in post- Association of a polymorphism in the promoter mortem brains of schizophrenic patients and control region of the serotonin 5-HT2C receptor gene with subjects in the present study. Among members of the tardive dyskinesia in patients with schizophrenia EGF family examined, EGF were specifically decreased ZJ Zhang, XB Zhang, WW Sha, XB Zhang, in the prefrontal cortex and striatum, where the dopa- GP Reynolds minergic neurons innervate. Conversely, receptor lev- els for EGF were increased in the same region. More- Tardive dyskinesia (TD) is a major side effect of over, the reduction in EGF was also seen in serum of chronic treatment with antipsychotic drugs. As the 5- schizophrenic patients, even in drug-naive patients. HT2C receptor is involved in motor function including However, chronic administration of haloperidol to rats production of dyskinesias, the authors have investi- had no effect on EGF levels. These findings suggest a gated whether functional polymorphisms of the pro- strong link between abnormal EGF receptor signaling moter region of the 5-HT2C receptor gene may be asso- and schizophrenia that might underlie the domami- ciated with TD. They studied 42 schizophrenic nergic dysfunction in this illness. patients with persistent TD, and 50 matched patients without dyskinesias, and identified a significant excess of one allelic variant in the TD group. As haplotypes Decreased phorbol ester binding in the containing this allele have higher promoter activity, parahippocampal gyrus from subjects with the authors conclude that genetic control of 5-HT2C schizophrenia is not associated with changes in receptor expression may contribute to susceptibility to protein kinase C drug-induced dyskinesias. E Scarr, G Pavey, PI Robinson, K Opeskin, DL Copolov, B Dean No occurrence of the glutamate transporter EAAT2 The authors further investigated previous findings of A206G polymorphism in schizophrenic subjects decreased phorbol ester binding in the parahippocam- M Catalano, C Lorenzi, L Bocchio, G Racagni pal gyrus from subjects with schizophrenia. Phorbol esters bind to protein kinase C, which can be important A relative glutamatergic hypofunction is suspected to in responses to neurotransmitters. Changes in phorbol be involved in schizophrenia. Recent findings support- ester binding were confirmed but there were no ing this hypothesis, and the possible candidate role for changes in levels of protein kinase C isoforms or the gene encoding the glutamate transporter EAAT2, enzyme activity. This raises the possibility that other prompted the authors to study the A(G transition in phorbol ester binding sites are altered in schizo- codon 206 (Ser(Asn) of this gene in 124 schizophrenics phrenia. and 50 healthy controls of Italian descent. Negative finding seems to exclude any association between this polymorphism and schizophrenia, at least in this sam- Genome-wide multipoint linkage analyses of ple. multiplex schizophrenia pedigrees from the oceanic nation of Palau B Devlin, SA Bacanu, K Roeder, F Reimherr, ORIGINAL RESEARCH ARTICLES P Wender, B Galke, D Novasad, A Chu, K TCuenco, Abnormal expression of epidermal growth factor S Tiobek, C Otto, W Byerley and its receptor in the forebrain and serum of The oceanic nation of Palau has been geographically schizophrenic patients and culturally isolated over most of its 2000-year his- T Futamura, K Toyooka, S Iritani, K Niizato, tory. To localize genetic variants affecting liability to R Nakamura, K Tsuchiya, T Someya, A Kakita, schizophrenia, the authors scanned the genomes of five H Takahashi, H Nawa large Palauan pedigrees using over 400 genetic mark- Abnormality in dopaminergic function has often been ers. They found significant and suggestive linkage sig- implicated as a cause of schizophrenia. Diffusible pro- nals on chromosomes 5 and 3, respectively. Their General Summary 666 results suggest there are multiple genes conferring lia- Imbalance in dopamine neurotransmission and inter- bility to schizophrenia even in this small island popu- action between dopaminergic and serotonergic systems lation. has been suggested as a predisposing factor in the pathophysiology of ADHD. Using haplotype-based Relationship between adverse effects of haplotype relative risk (HHRR) and transmission dis- antipsychotic treatment and dopamine D2 receptor equilibrium test (TDT) analyses, a significant preferen- polymorphisms in patients with schizophrenia tial transmission of the allele 861G of the serotonergic R Kaiser, PB Tremblay, F Klufmo¨ ller, I Roots, receptor 5-HTR1B in the total sample (for HHRR; c2 = J Brockmo¨ ller 7.4, P = 0.0065 and TDT; c2 = 6.4, P = 0.014) was observed. These preliminary data suggest an important Genetic variants in the dopamine D receptor (DRD2) 2 role for the serotonergic system in the development gene may modulate the severity of adverse effects of of ADHD. antipsychotics. In a prospective naturalistic study in 665 Caucasian schizophrenic patients, the authors × found no significant association between in tensity of Antiepileptic drugs and agents that inhibit voltage- acute dystonia, extrapyramidal symptoms, akathisia, gated sodium channels prevent NMDA antagonist and tardive dyskinesia and nine DRD2 polymorphisms. neurotoxicity Sequencing of the DRD2 coding region including exon– NB Farber, XP Jiang, C Heinkel, B Nemmers intron junctions revealed no new amino acid variants. Antagonists of the NMDA glutamate receptor produce Higher scores of self-reported schizotype in healthy a dishibitory state that causes excessive stimulation of young males carrying the COMT high activity allele cerebrocortical neurons, resulting in psychosis and D Avramopoulos, NC Stefanis, I Hantoumi, neurotoxicity. The authors report that several anticon- N Smyrnis, I Evdokimidis, CN Stefanis vulsants through different mechanisms can prevent the neurotoxicity associated with this NMDA receptor The authors tested the hypothesis that COMT genotype hypofunction (NRHypo) state. These agents might have for the functional Val158Met polymorphism might therapeutic benefits for conditions (eg Alzheimer’s dis- contribute to the variance of self-reported schizotypy ease, schizophrenia, bipolar disorder) in which an in the normal population. Results showed that self- NRHypo state may exist. reported schizotypy scores were significantly related to COMT genotype with individuals homozygous for the high activity allele showing the highest scores. This A genome-wide scan shows significant linkage adds to the list of evidence that COMT or a nearby gene between bipolar disorder and chromosome 12q24.3 in linkage disequilibrium is involved in the pathogen- and suggestive linkage to chromosomes 1p22–21, esis of schizophrenia. 4p16, 6q14–22, 10q26 and 16p13.3 H Ewald, T Flint, TA Kruse, O Mors A meta-analysis of the association between DRD4 The authors presented results of a genome scan on two polymorphism and Novelty Seeking families with bipolar disorder using 613 microsatellite AN Kluger, Z Siegfried, RP Ebstein markers. Significant linkage was found at D12S1639 An initial, exciting report about a correlation between with a parametric lod score of 3.42 (genome-wide P- DRD4 polymorphism and personality were followed by value 0.0417). Marker D1S216 yielded a parametric, inconsistent reports. To assess the evidence regarding affecteds-only lod score of 2.75 (genome-wide P-value the association between DRD4 polymorphism and Nov- 0.1622), which were supported by non-parametric elty Seeking, the authors combined, statistically, 20 multipoint analyses. Additional loci on chromosomes studies (n = 3907). This meta-analysis suggests that, on 4p, 6q, 10q and 16p yielded parametric lod scores average, there is no association between DRD4 poly- around or above 2. morphism and Novelty Seeking. However, a weak or complex association may exist—a possibility that requires further research. Novel polymorphisms in the somatostatin receptor 5 (SSTR5) gene associated with bipolar affective Serotonergic system and attention deficit disorder hyperactivity disorder (ADHD): a potential M Nyegaard, AD Børglum, TG Bruun, DA Collier, susceptibility locus at the 5-HT1B receptor gene in C Russ, O Mors, H Ewald, TA Kruse 273 nuclear families from a multi-centre sample The SSTR5 gene is a candidate gene for bipolar affect- Z Hawi, M Dring, A Kirley, D Foley, L Kent, ive disorder (BPAD). SSTR5 forms functional heterodi- N Craddock, P Asherson, S Curran, A Gould, mers with DRD2, a major target of neuroleptic treat- S Richards, D Lawson, H Pay, D Turic, K Langley, ments in psychiatric disorders. The gene was M Owen, M O’Donovan, A Thapar, M Fitzgerald, sequenced in bipolar patients and 11 novel polymor- M Gill phisms were found. Significant association between Attention deficit hyperactivity disorder (ADHD) is a different SNPs in SSTR5 and bipolar disorder was highly heritable disorder affecting school-age children. found in a Danish and a British case-control
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