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CAG repeat containing genes and schizophrenia: An association study
985
BIOL. PSYCHIATRY
139-471
Induction of neurotensln mRNA In rat brain after treatment with antipsychotic drugs: A predictive model for motor side effects?
A. Schone, J.E. Leysen, A. Berod, M. Oussaillant, W. Rostene. Dept. BlochemicsJ Pharmacology. Janssen Research Foundation, Beerse, Belgium and INSERM UO.339, Paris, France Neurotensln (NT) mRNA was reported to be Increased In the shell of the nucleus accumbens of the rat after treatment with both c10zapine and haloperidol, whereas NT mRNA was Increased In the dorsolateral part of the caudate nucleus only after haloperidol treatment. It was suggested that this model could d'tfferentiate typical lrom atypical antipsychotics. The present study was aimed to further explore Its reliability. Therefore, In vivo neurotransmitter receptor occupancy, measured ex vivo by quantitative autoradiography, was compared with levels of NT mRNA measured by In situ hybridization In rat brain after treatment with twelve antipsychotlcs of different pharmacological and clinical classes, Dose-occupancy curves (0.01-10 mglkg) were measured lor the 0c• cupancy of all receptors with which the compounds Interact. In adjacent sections, significant differences In NT mRNA density were observed In the caudate nucleus both among the groups 01 typical and atypical entlpsy· choties. Correlations between NT mRNA expression and clinical classes of the compounds are Investigated, potential roles played by the occupancy of particular receptors are analysed and the validity of the model Is discussed.
[3948J
Association between novelty seeking and the dopamine 03 receptor gene In bipolar patients
Luc Staner', Christiane Hilger 2 , Fra"9ois Hentges S , Jose Monreal 1, Annlck Hoffmann s, Marianne Couturier' , Olivier LeBon 4 , G. Stefos ' , J. Mendlewlcz 5. ' Department of PsycNatry, Grand Duchy of Luxembourg, 2 Public Research Center Henri Tudor, Grand Duchy of Luxembourg, 3 Laboratory of Immunology and Allergology. Hospital Center of Luxembourg, Grand Duchy of Luxembourg, 4 Department of Psychiatry, university Hospital Brugmann, Belgium, 5 Department of Psychiatry, Erasme Hospital, Free University of Brussels, Belgium In hiS tridimensional theory of personality, Cloninger posits that three heritable
traits are determined in part by a specific neurotransmitter, and are supposed
to undel1y basic temperaments In human beings. OR04 has recently been associated with novelty seekIng (NS) In healthy controls (HC). In this study, 37 BP patients were examined lor a possible association between NS and the OR04 exon III polymorphism as well as the BaA exon I polymorphism of the OR03 gene. Patients were diagnosed according to ROC using the SAOS and had to experience a period of euthymia of at least 2 months before fulfilling the TPO. Results show an association between NS and polymorphlsms 01 ORD3 In BP patients; carriers of allele 1 showed lower NS values compared to patients without allele (13.23 % 4,9 versus 17.34 % 4.2; p = 0.014). In contrast to previous studies with HC, the association between OR04 polymorphism was not replicated In our BP patients. Although this study needs replication before drawing ftrm conclusions, It can be hypothesized that 03 and D4 receptors are differently Implicated In NS expression In BP patients and HC.
139-491
Poster session n
1997:42: 1S-297S
Polyglutamln containing proteins In schizophrenia
A. Joober, C. Benkelfat, J.L Mandel, I. Lopes-Cendes, S. LsI, P. Lalonde, A. Labelle, R. Palmour, G. O'Orlscoll, G.A. Rouleau. Douglas Hospital Research Centre & Centre lor R8S88rch In Neurosciences, McGiff University. Montreal, canada Dynamic mutations (OM) are a newly described type of mutation character· Ized by an abnormal expansion 01 trinucleotide repeats (TNRs) In individual genes. They are Involved In several neurodegenerative diseases showing genetic anticipation. Because: (I) OM could explaln many of the genetic epidemiology characteristics of schizophrenia; (Ii) anticipation was reported In schizophrenia, and; (III) all diseases caused by OM Involve the CNS, It has been hypothesized that OM can playa role in schizophrenia. At the protein level, CAG repeats, the most common TNR causing diseases, are translated as polyglutamine stretches. Recently, a monoclonal antibody (1 C2) recog• nizing expanded polyglutamin peptides was designed and used to detect expanded poIyglutamlne stretches In diseases suspected to be caused by OM. We are using the 1C2 antibody to detect expanded polyglutamlne peptldes In a population of schizophrenic patients. To date, proteins from 32 schizophrenic patients have been extracted and analyzed by westemblots
and Immunodetection techniques. Two unrelated patients shoWed a band corresponding to a protein with a molecular weight different from all other proteins reported In diseases caused by CAG repeat containing genes. 40 subjects with non-linked spinocerebeliar ataxia were negative for this band. These findings Indicate that proteins containing expanded poIyglutamine stretches might playa role In schizophrenia.
139-50
I An CAG repeat containing genes and schizophrenia: association study
R. Joober, C. Benke!lat, R. Lefrontlere, S. Lal, P. Lalonde. A. Labelle, G. Tureckl, R. Palmour, G. O'Oriscoll, GoA Rouleau. Douglas Hospital Research Centre & Centre ror Research In Neurosciences. McGill University. Montreal, Canada Dynamic mutations are a newly described type of mutation characterized by an abnormal expansion 01 trinucleotide repeats In individual genes. Recently, expansions of CAG repeats (CAGr) (in the range of Huntington gene expansion) have been lound to be over represented in schizophrenic patients. To further test this hypothesis, we are studying genes or expr8SSed sequence tags (ESTs) containing CAGr in three groups of subjects: severely affected and neuroleptic-resistant schizophrenic patients (n • 62). mildly affected and neuroleptic responsive schizophrenic patients (n • 46) and an ethnically matched control group (n • SO). CAGr-containing genes and ESTs are Identified through a genome data base search. To date. we have Identified 14 EST. Two of these tumed out to be known genes: the TATA binding protein, a general transcription co-factor, and the ocatamer transcription factor (N-QCT3). 10 ESTs gave a PeR product with a sma1l size equivalent to the predicted one and were run on a denaturing poIyacry\amjde gel. Four 01 these were found to be polymorphic. 4 ESTs gave a PeR product with a high size Incompatible with polyacrylamide gel resolution. These ESTs are being analyzed by RT-PCR. Results 01 association between polymorphic: CAGr-containing ESTs end schizophrenia will be presented and diSCUssed.
139-51
I
A study of association between schizophrenia and polymorphism at the neurotrophln-3 gene
Y.S. Lee, J.H. Han, Y.G. Cha!. E.K. Chung, Y.H. Joo, H.S. Kim, J.S. lee, S.H. Yang. Yangin Mental Hospital, Yongin-sJ, Korea We investigated the distribution of neurotrophin-3 (NT-3) gene's polymorphic mar1
139-521
Two-trait-Iocus linkage analysis: An application to schizophrenia
T. FOreder 1 , H,N. Aschauer 3 , K. Meszaros', E. Lenzlnger s• K. Hornik' K. Fuchs 2, W. Sleghart 2 , L Yang·, H.W. MoIses·, S. Kasper s• 'Instituf Ai Stat/stik und WahrscheinJichkeltstheori8, V'18fIflS University of Technology, Austria. 3 University Hospital for Psychiatry, Departmsnt of General ' Psychiatry, Vienna, Austria, 2 University Hospital lor Psychiatry, DePBrtmert of BiochemicsJ Psychiatry. Vienna, Austria, •Department of Psychiatry, University Hospital Kiel, Germany Simulation studies Indicate that two-trait·locus, two-marl
BIOL. PSYCHIATRY
139-471
Induction of neurotensln mRNA In rat brain after treatment with antipsychotic drugs: A predictive model for motor side effects?
A. Schone, J.E. Leysen, A. Berod, M. Oussaillant, W. Rostene. Dept. BlochemicsJ Pharmacology. Janssen Research Foundation, Beerse, Belgium and INSERM UO.339, Paris, France Neurotensln (NT) mRNA was reported to be Increased In the shell of the nucleus accumbens of the rat after treatment with both c10zapine and haloperidol, whereas NT mRNA was Increased In the dorsolateral part of the caudate nucleus only after haloperidol treatment. It was suggested that this model could d'tfferentiate typical lrom atypical antipsychotics. The present study was aimed to further explore Its reliability. Therefore, In vivo neurotransmitter receptor occupancy, measured ex vivo by quantitative autoradiography, was compared with levels of NT mRNA measured by In situ hybridization In rat brain after treatment with twelve antipsychotlcs of different pharmacological and clinical classes, Dose-occupancy curves (0.01-10 mglkg) were measured lor the 0c• cupancy of all receptors with which the compounds Interact. In adjacent sections, significant differences In NT mRNA density were observed In the caudate nucleus both among the groups 01 typical and atypical entlpsy· choties. Correlations between NT mRNA expression and clinical classes of the compounds are Investigated, potential roles played by the occupancy of particular receptors are analysed and the validity of the model Is discussed.
[3948J
Association between novelty seeking and the dopamine 03 receptor gene In bipolar patients
Luc Staner', Christiane Hilger 2 , Fra"9ois Hentges S , Jose Monreal 1, Annlck Hoffmann s, Marianne Couturier' , Olivier LeBon 4 , G. Stefos ' , J. Mendlewlcz 5. ' Department of PsycNatry, Grand Duchy of Luxembourg, 2 Public Research Center Henri Tudor, Grand Duchy of Luxembourg, 3 Laboratory of Immunology and Allergology. Hospital Center of Luxembourg, Grand Duchy of Luxembourg, 4 Department of Psychiatry, university Hospital Brugmann, Belgium, 5 Department of Psychiatry, Erasme Hospital, Free University of Brussels, Belgium In hiS tridimensional theory of personality, Cloninger posits that three heritable
traits are determined in part by a specific neurotransmitter, and are supposed
to undel1y basic temperaments In human beings. OR04 has recently been associated with novelty seekIng (NS) In healthy controls (HC). In this study, 37 BP patients were examined lor a possible association between NS and the OR04 exon III polymorphism as well as the BaA exon I polymorphism of the OR03 gene. Patients were diagnosed according to ROC using the SAOS and had to experience a period of euthymia of at least 2 months before fulfilling the TPO. Results show an association between NS and polymorphlsms 01 ORD3 In BP patients; carriers of allele 1 showed lower NS values compared to patients without allele (13.23 % 4,9 versus 17.34 % 4.2; p = 0.014). In contrast to previous studies with HC, the association between OR04 polymorphism was not replicated In our BP patients. Although this study needs replication before drawing ftrm conclusions, It can be hypothesized that 03 and D4 receptors are differently Implicated In NS expression In BP patients and HC.
139-491
Poster session n
1997:42: 1S-297S
Polyglutamln containing proteins In schizophrenia
A. Joober, C. Benkelfat, J.L Mandel, I. Lopes-Cendes, S. LsI, P. Lalonde, A. Labelle, R. Palmour, G. O'Orlscoll, G.A. Rouleau. Douglas Hospital Research Centre & Centre lor R8S88rch In Neurosciences, McGiff University. Montreal, canada Dynamic mutations (OM) are a newly described type of mutation character· Ized by an abnormal expansion 01 trinucleotide repeats (TNRs) In individual genes. They are Involved In several neurodegenerative diseases showing genetic anticipation. Because: (I) OM could explaln many of the genetic epidemiology characteristics of schizophrenia; (Ii) anticipation was reported In schizophrenia, and; (III) all diseases caused by OM Involve the CNS, It has been hypothesized that OM can playa role in schizophrenia. At the protein level, CAG repeats, the most common TNR causing diseases, are translated as polyglutamine stretches. Recently, a monoclonal antibody (1 C2) recog• nizing expanded polyglutamin peptides was designed and used to detect expanded poIyglutamlne stretches In diseases suspected to be caused by OM. We are using the 1C2 antibody to detect expanded polyglutamlne peptldes In a population of schizophrenic patients. To date, proteins from 32 schizophrenic patients have been extracted and analyzed by westemblots
and Immunodetection techniques. Two unrelated patients shoWed a band corresponding to a protein with a molecular weight different from all other proteins reported In diseases caused by CAG repeat containing genes. 40 subjects with non-linked spinocerebeliar ataxia were negative for this band. These findings Indicate that proteins containing expanded poIyglutamine stretches might playa role In schizophrenia.
139-50
I An CAG repeat containing genes and schizophrenia: association study
R. Joober, C. Benke!lat, R. Lefrontlere, S. Lal, P. Lalonde. A. Labelle, G. Tureckl, R. Palmour, G. O'Oriscoll, GoA Rouleau. Douglas Hospital Research Centre & Centre ror Research In Neurosciences. McGill University. Montreal, Canada Dynamic mutations are a newly described type of mutation characterized by an abnormal expansion 01 trinucleotide repeats In individual genes. Recently, expansions of CAG repeats (CAGr) (in the range of Huntington gene expansion) have been lound to be over represented in schizophrenic patients. To further test this hypothesis, we are studying genes or expr8SSed sequence tags (ESTs) containing CAGr in three groups of subjects: severely affected and neuroleptic-resistant schizophrenic patients (n • 62). mildly affected and neuroleptic responsive schizophrenic patients (n • 46) and an ethnically matched control group (n • SO). CAGr-containing genes and ESTs are Identified through a genome data base search. To date. we have Identified 14 EST. Two of these tumed out to be known genes: the TATA binding protein, a general transcription co-factor, and the ocatamer transcription factor (N-QCT3). 10 ESTs gave a PeR product with a sma1l size equivalent to the predicted one and were run on a denaturing poIyacry\amjde gel. Four 01 these were found to be polymorphic. 4 ESTs gave a PeR product with a high size Incompatible with polyacrylamide gel resolution. These ESTs are being analyzed by RT-PCR. Results 01 association between polymorphic: CAGr-containing ESTs end schizophrenia will be presented and diSCUssed.
139-51
I
A study of association between schizophrenia and polymorphism at the neurotrophln-3 gene
Y.S. Lee, J.H. Han, Y.G. Cha!. E.K. Chung, Y.H. Joo, H.S. Kim, J.S. lee, S.H. Yang. Yangin Mental Hospital, Yongin-sJ, Korea We investigated the distribution of neurotrophin-3 (NT-3) gene's polymorphic mar1
139-521
Two-trait-Iocus linkage analysis: An application to schizophrenia
T. FOreder 1 , H,N. Aschauer 3 , K. Meszaros', E. Lenzlnger s• K. Hornik' K. Fuchs 2, W. Sleghart 2 , L Yang·, H.W. MoIses·, S. Kasper s• 'Instituf Ai Stat/stik und WahrscheinJichkeltstheori8, V'18fIflS University of Technology, Austria. 3 University Hospital for Psychiatry, Departmsnt of General ' Psychiatry, Vienna, Austria, 2 University Hospital lor Psychiatry, DePBrtmert of BiochemicsJ Psychiatry. Vienna, Austria, •Department of Psychiatry, University Hospital Kiel, Germany Simulation studies Indicate that two-trait·locus, two-marl