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18 results on '"Toliat, M.R."'

1. Biallelic MAD2L1BP (p31comet) mutation is associated with mosaic aneuploidy and juvenile granulosa cell tumors.

Author

Abdel-Salam, G.M.H., Hellmuth, S., Gradhand, E., Käseberg, S., Winter, J., Pabst, A.S., Eid, M.M., Thiele, H., Nürnberg, P., Budde, B.S., Toliat, M.R., Brecht, I.B., Schroeder, C., Gschwind, A., Ossowski, S., Häuser, F., Rossmann, H., Abdel-Hamid, M.S., Hegazy, I., Mohamed, A.G., Schneider, D.T., Bertoli-Avella, A., Bauer, P., Pearring, J.N., Pfundt, R.P., Hoischen, A., Gilissen, C.F.H.A., Strand, D., Zechner, U., Tashkandi, S.A., Faqeih, E.A., Stemmann, O., Strand, S., Bolz, H.J., Abdel-Salam, G.M.H., Hellmuth, S., Gradhand, E., Käseberg, S., Winter, J., Pabst, A.S., Eid, M.M., Thiele, H., Nürnberg, P., Budde, B.S., Toliat, M.R., Brecht, I.B., Schroeder, C., Gschwind, A., Ossowski, S., Häuser, F., Rossmann, H., Abdel-Hamid, M.S., Hegazy, I., Mohamed, A.G., Schneider, D.T., Bertoli-Avella, A., Bauer, P., Pearring, J.N., Pfundt, R.P., Hoischen, A., Gilissen, C.F.H.A., Strand, D., Zechner, U., Tashkandi, S.A., Faqeih, E.A., Stemmann, O., Strand, S., and Bolz, H.J.

Abstract

Contains fulltext : 299854.pdf (Publisher’s version ) (Open Access), MAD2L1BP-encoded p31comet mediates Trip13-dependent disassembly of Mad2- and Rev7-containing complexes and, through this antagonism, promotes timely spindle assembly checkpoint (SAC) silencing, faithful chromosome segregation, insulin signaling, and homology-directed repair (HDR) of DNA double-strand breaks. We identified a homozygous MAD2L1BP nonsense variant, R253*, in 2 siblings with microcephaly, epileptic encephalopathy, and juvenile granulosa cell tumors of ovary and testis. Patient-derived cells exhibited high-grade mosaic variegated aneuploidy, slowed-down proliferation, and instability of truncated p31comet mRNA and protein. Corresponding recombinant p31comet was defective in Trip13, Mad2, and Rev7 binding and unable to support SAC silencing or HDR. Furthermore, C-terminal truncation abrogated an identified interaction of p31comet with tp53. Another homozygous truncation, R227*, detected in an early-deceased patient with low-level aneuploidy, severe epileptic encephalopathy, and frequent blood glucose elevations, likely corresponds to complete loss of function, as in Mad2l1bp-/- mice. Thus, human mutations of p31comet are linked to aneuploidy and tumor predisposition.

Published
2023

3. Comprehensive molecular analysis of 61 Egyptian families with hereditary nonsyndromic hearing loss

Author

Budde, B.S., Aly, M.A., Mohamed, M.R., Breß, A., Altmüller, J., Motameny, S., Kawalia, A., Thiele, H., Konrad, K., Becker, C., Toliat, M.R., Nürnberg, G., Sayed, E.A.F., Mohamed, E.S., Pfister, M., and Nürnberg, P.

Subjects
Technology Platforms
Abstract

Nonsyndromic hearing loss is an extremely heterogeneous disorder. Thus, clinical diagnostics is challenging, in particular due to differences in the etiology of hearing loss between populations. With this study, we wanted to elucidate the genetic basis of hearing loss in 61 consanguineous Egyptian families. In 25 families, linkage analysis was used as a prescreening to identify regions for targeted sequencing of candidate genes. Initially, the coding regions of 12 and later of 94 genes associated with hearing loss were enriched and subjected to massively parallel sequencing (MPS) with diagnostic yields of 36% and 75%, respectively. Causative variants were identified in 48 families (79%). They were found in 23 different genes with the majority being located in MYO15A (15.3%), SLC26A4 (9.7%), GJB2 (8.3%), and MYO7A (6.4%). As many as 32 variants were novel ones at the time of detection. Five variants were shared by two, three, or even four families. Our study provides a first survey of the mutational spectrum of deaf patients in Egypt revealing less GJB2 variants than in many European populations. It underlines the value of targeted enrichment of well-selected deafness genes in combination with MPS in the diagnostics of this frequent and genetically heterogeneous disorder.

Published
2020

4. Rare gene deletions in genetic generalized and Rolandic epilepsies

Author

Jabbari, K. (Kamel), Bobbili, D.R. (Dheeraj R.), Lal, D. (Dennis), Reinthaler, E.M. (Eva M.), Schubert, J. (Julian), Wolking, S. (Stefan), Sinha, V. (Vishal), Motameny, S. (Susanne), Thiele, H. (Holger), Kawalia, A. (Amit), Altmüller, J. (Janine), Toliat, M.R. (Mohammad Reza), Kraaij, R. (Robert), van Rooij, J. (Jeroen), Uitterlinden, A.G. (André G.), Ikram, M.A. (Arfan), Zara, F. (Federico), Lehesjoki, A.E., Krause, R. (Roland), Zimprich, F. (Fritz), Sander, T. (Thomas), Neubauer, B.A. (Bernd A.), May, P. (Patrick), Lerche, H. (Holger), Nürnberg, P. (Peter), Jabbari, K. (Kamel), Bobbili, D.R. (Dheeraj R.), Lal, D. (Dennis), Reinthaler, E.M. (Eva M.), Schubert, J. (Julian), Wolking, S. (Stefan), Sinha, V. (Vishal), Motameny, S. (Susanne), Thiele, H. (Holger), Kawalia, A. (Amit), Altmüller, J. (Janine), Toliat, M.R. (Mohammad Reza), Kraaij, R. (Robert), van Rooij, J. (Jeroen), Uitterlinden, A.G. (André G.), Ikram, M.A. (Arfan), Zara, F. (Federico), Lehesjoki, A.E., Krause, R. (Roland), Zimprich, F. (Fritz), Sander, T. (Thomas), Neubauer, B.A. (Bernd A.), May, P. (Patrick), Lerche, H. (Holger), and Nürnberg, P. (Peter)

Abstract

Genetic Generalized Epilepsy (GGE) and benign epilepsy with centro-temporal spikes or Rolandic Epilepsy (RE) are common forms of genetic epilepsies. Rare copy number variants have been recognized as important risk factors in brain disorders. We performed a systematic survey of rare deletions affecting protein-coding genes derived from exome data of patients with common forms of genetic epilepsies. We analysed exomes from 390 European patients (196 GGE and 194 RE) and 572 population controls to identify low-frequency genic deletions. We found that 75 (32 GGE and 43 RE) patients out of 390, i.e. ~19%, carried rare genic deletions. In particular, large deletions (<400 kb) represent a higher burden in both GGE and RE syndromes as compared to controls. The detected low-frequency deletions (1) share genes with brain-expressed exons that are under negative select

Published
2018
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5. Exon-disrupting deletions ofNRXN1in idiopathic generalized epilepsy

Author

Møller, R.S., Weber, Y.G., Klitten, L.L., Trucks, H., Muhle, H., Kunz, W.S., Mefford, H.C., Franke, A., Kautza, M., Wolf, P., Dennig, D., Schreiber, S., Rückert, I.M., Wichmann, H.E., Ernst, J.P., Schurmann, C., Grabe, H.J., Tommerup, N., Stephani, U., Lerche, H., Hjalgrim, H., Helbig, I., Sander, T., Zimprich, F., Mörzinger, M., Feucht, M., Suls, A., Weckhuysen, S., Claes, L., Deprez, L., Smets, K., Van Dyck, T., Deconinck, T., De Jonghe, P., Velizarova, R., Dimova, P., Radionova, M., Tournev, I., Kancheva, D., Kaneva, R., Jordanova, A., Kjelgaard, D.B., Lehesjoki, A.E., Siren, A., Baulac, S., Leguern, E., Von Spiczak, S., Ostertag, P., Leber, M., Leu, C., Toliat, M.R., Nürnberg, P., Hempelmann, A., Rüschendorf, F., Elger, C.E., Kleefuß Lie, A.A., Surges, R., Gaus, V., Janz, D., Schmitz, B., Klein, K.M., Reif, P.S., Oertel, W.H., Hamer, H.M., Rosenow, F., Becker, F., Marini, C., Guerrini, R., Mei, D., Norci, V., Zara, F., Striano, P., Robbiano, A., Pezzella, M., Bianchi, A., Gambardella, A., Tinuper, P., La Neve, A., Capovilla, G., Vigliano, P., Crichiutti, G., Vanadia, F., Vignoli, A., Coppola, A., Striano, S., Giallonardo, M.T., Franceschetti, S., Belcastro, V., Benna, P., Coppola, G., De Palo, A., Ferlazzo, E., Vecchi, M., Martinelli, V., Bisulli, F., Beccaria, F., Del Giudice, E., Mancardi, M., Stranci, G., Scabar, A., Gobbi, G., Giordano, I., Koeleman, B.P.C., De Kovel, C., Lindhout, D., De Haan, G.J., Ozbeck, U., Bebek, N., Baykan, B., Ozdemir, O., Ugur, S., Kocasoy Orhan, E., Yücesan, E., Cine, N., Gokyigit, A., Gurses, C., Gul, G., Yapici, Z., Ozkara, C., Caglayan, H., Yalcin, O., Yalcin, D., Turkdogan, D., Dizdarer, G., Agan, K., R. S. Møller, Y. G. Weber, L. L. Klitten, H. Truck, H. Muhle, W. S. Kunz, H. C. Mefford, A. Franke, M. Kautza, P. Wolf, D. Dennig, S. Schreiber, I. Rückert, H. Wichmann, J. P. Ernst, C. Schurmann, H. J. Grabe, N. Tommerup, U. Stephani, H. Lerche, H. Hjalgrim, I. Helbig, T. Sander, P. Tinuper, F. Bisulli, EPICURE Consortium, Suls, Arvid, Weckhuysen, Sarah, Claes, Godelieve, Deprez, Liesbet, Smets, Katrien, Van Dyck, Tine, Deconinck, Tine, De Jonghe, Peter, Jordanova, Albena, Møller, R, Weber, Yg, Klitten, Ll, Trucks, H, Muhle, H, Kunz, W, Mefford, Hc, Franke, A, Kautza, M, Wolf, P, Dennig, D, Schreiber, S, Rückert, Im, Wichmann, He, Ernst, Jp, Schurmann, C, Grabe, Hj, Tommerup, N, Stephani, U, Lerche, H, Hjalgrim, H, Helbig, I, Sander, T, Epicure, Consortium, DEL GIUDICE, Ennio, Coppola, Antonietta, and YÜCESAN, EMRAH

Subjects
Male, Idiopathic generalized epilepsy, Neuronal, Idiopathic Generalized Epilepsy, 1q21, 1 Microdeletion, Two-hit Hypothesis, Nrxn1, Neuropsychological Tests, Immunoglobulin E, Cell Adhesion Molecules, Neuronal/genetics, Adult, Age of Onset, Anticonvulsant, Exon, 1q21.1 microdeletion, Exons/genetics, Odds Ratio, Nerve Tissue Proteins/genetics, Copy-number variation, Valproic Acid/therapeutic use, Age of Onset, Neural Cell Adhesion Molecules, genetics, DNA Copy Number Variations, Electroencephalography, Epilepsy, Genetics, biology, Triazines, Anticonvulsants/therapeutic use, Electroencephalography, genetics, Family, Female, Fructose, Exons, Middle Aged, Settore MED/39 - Neuropsichiatria Infantile, Pedigree, therapeutic use, Valproic Acid, Neurology, Settore MED/26 - Neurologia, Anticonvulsants, Epilepsy, Generalized, Female, Adult, Case-Control Studies, Cell Adhesion Molecules, Neuronal, DNA Copy Number Variations, Family, Fructose, Gene Deletion, Genotype, Humans, Infant, Microarray Analysis, Nerve Tissue Proteins, Valproic Acid, analogs /&/ derivatives/therapeutic use, Gene Deletion, Genotype, Humans, Infant, Male, Microarray Analysis, Middle Aged, Nerve Tissue Protein, therapeutic use, Case-Control Studies, Cell Adhesion Molecule, drug therapy/genetics/psychology, Exon, genetics, Neuropsychological Tests, Odds Ratio, Pedigree, Triazine, Lamotrigine, NRXN1, Topiramate, Epilepsy, Generalized/drug therapy, medicine, Allele, Biology, Gene, Generalized, Point mutation, Calcium-Binding Proteins, Odds ratio, medicine.disease, Triazines/therapeutic use, Settore MED/03 - Genetica Medica, therapeutic use, biology.protein, Fructose/analogs & derivatives, Human medicine, Neurology (clinical), Two-hit hypothesis
Abstract

Summary Purpose Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs). Methods We screened for deletions involving the NRXN1 gene in 1,569 patients with IGE and 6,201 controls using high-density oligonucleotide microarrays. Key Findings We identified exon-disrupting deletions of NRXN1 in 5 of 1,569 patients with IGE and 2 of 6,201 control individuals (p = 0.0049; odds ratio (OR) 9.91, 95% confidence interval (CI) 1.92–51.12). A complex familial segregation pattern in the IGE families was observed, suggesting that heterozygous NRXN1 deletions are susceptibility variants. Intriguingly, we identified a second large copy number variant in three of five index patients, supporting an involvement of heterogeneous susceptibility alleles in the etiology of IGE. Significance We conclude that exon-disrupting deletions of NRXN1 represent a genetic risk factor in the genetically complex predisposition of common IGE syndromes.

Published
2013

6. Meta-analysis of genome-wide association studies and network analysis-based integration with gene expression data identify new suggestive loci and unravel a Wnt-centric network associated with Dupuytren's disease

Author

Becker, K., Siegert, S., Toliat, M.R., Du, J., Casper, R., Dolmans, G.H., Werker, P.M., Tinschert, S., Franke, A., Gieger, C., Strauch, K., Nothnagel, M., Nürnberg, P., and Hennies, H.C.

Abstract

Dupuytren´s disease, a fibromatosis of the connective tissue in the palm, is a common complex disease with a strong genetic component. Up to date nine genetic loci have been found to be associated with the disease. Six of these loci contain genes that code for Wnt signalling proteins. In spite of this striking first insight into the genetic factors in Dupuytren´s disease, much of the inherited risk in Dupuytren´s disease still needs to be discovered. The already identified loci jointly explain ~1% of the heritability in this disease. To further elucidate the genetic basis of Dupuytren´s disease, we performed a genome-wide meta-analysis combining three genome-wide association study (GWAS) data sets, comprising 1,580 cases and 4,480 controls. We corroborated all nine previously identified loci, six of these with genome-wide significance (p-value < 5x10-8). In addition, we identified 14 new suggestive loci (p-value < 10-5). Intriguingly, several of these new loci contain genes associated with Wnt signalling and therefore represent excellent candidates for replication. Next, we compared whole-transcriptome data between patient- and control-derived tissue samples and found the Wnt/β-catenin pathway to be the top deregulated pathway in patient samples. We then conducted network and pathway analyses in order to identify protein networks that are enriched for genes highlighted in the GWAS meta-analysis and expression data sets. We found further evidence that the Wnt signalling pathways in conjunction with other pathways may play a critical role in Dupuytren´s disease.

Published
2016

7. Wnt signaling and Dupuytren's disease

Author

Dolmans, G.H., Werker, P.M., Hennies, H.C., Furniss, D., Festen, E.A., Franke, L., Becker, K., van der Vlies, P., Wolffenbuttel, B.H., Tinschert, S., Toliat, M.R., Nothnagel, M., Franke, A., Klopp, N., Wichmann, H.-E., Nürnberg, P., Giele, H., Ophoff, R.A., Wijmenga, C, Dutch Dupuytren Study Group (), German Dupuytren Study Group (), LifeLines Cohort Study (), and BSSH-GODD Consortium ()

Subjects
Genetic susceptibility, Contracture, Catenin, Association, Management, Expression, Variants
Abstract

BACKGROUND: Dupuytren's disease is a benign fibromatosis of the hands and fingers that leads to flexion contractures. We hypothesized that multiple genetic and environmental factors influence susceptibility to this disease and sought to identify susceptibility genes to better understand its pathogenesis. METHODS: We conducted a genomewide association study of 960 Dutch persons with Dupuytren's disease and 3117 controls (the discovery set) to test for association between the disease and genetic markers. We tested the 35 single-nucleotide polymorphisms (SNPs) most strongly associated with Dupuytren's disease (P

Published
2011

8. tRNA splicing endonuclease mutations cause pontocerebellar hypoplasia.

Author

Budde, B., Namavar, Y., Barth, P.G., Poll-The, B.T., Nurnberg, G., Becker, C., Ruissen, F. van, Weterman, M.A.J., Fluiter, K., Beek, E.T. te, Aronica, E., Knaap, M.S. van der, Hohne, W., Toliat, M.R., Crow, Y.J., Steinling, M., Voit, T., Roelenso, F., Brussel, W., Brockmann, K., Kyllerman, M., Boltshauser, E., Hammersen, G., Willemsen, M.A.A.P., Basel-Vanagaite, L., Krageloh-Mann, I., Vries, L.S. de, Sztriha, L., Muntoni, F., Ferrie, C.D., Battini, R., Hennekam, R.C.M., Grillo, E., Beemer, F.A., Stoets, L.M., Wollnik, B., Nurnberg, P., Baas, F., Budde, B., Namavar, Y., Barth, P.G., Poll-The, B.T., Nurnberg, G., Becker, C., Ruissen, F. van, Weterman, M.A.J., Fluiter, K., Beek, E.T. te, Aronica, E., Knaap, M.S. van der, Hohne, W., Toliat, M.R., Crow, Y.J., Steinling, M., Voit, T., Roelenso, F., Brussel, W., Brockmann, K., Kyllerman, M., Boltshauser, E., Hammersen, G., Willemsen, M.A.A.P., Basel-Vanagaite, L., Krageloh-Mann, I., Vries, L.S. de, Sztriha, L., Muntoni, F., Ferrie, C.D., Battini, R., Hennekam, R.C.M., Grillo, E., Beemer, F.A., Stoets, L.M., Wollnik, B., Nurnberg, P., and Baas, F.

Abstract

Contains fulltext : 69211.pdf (publisher's version ) (Closed access), Pontocerebellar hypoplasias (PCH) represent a group of neurodegenerative autosomal recessive disorders with prenatal onset, atrophy or hypoplasia of the cerebellum, hypoplasia of the ventral pons, microcephaly, variable neocortical atrophy and severe mental and motor impairments. In two subtypes, PCH2 and PCH4, we identified mutations in three of the four different subunits of the tRNA-splicing endonuclease complex. Our findings point to RNA processing as a new basic cellular impairment in neurological disorders.

Published
2008

14. New strategies for efficient typing of HLA class-II loci DQB1 and DRB1 by using PyrosequencingTM.

Author

Entz, P., Toliat, M.R., Hampe, J., Valentonyte, R., Jenisch, S., Nürnberg, P., and Nagy, M.

Subjects
*HLA histocompatibility antigens, *DISEASE risk factors, *GENETIC polymorphisms, *POLYMERASE chain reaction, *CHROMOSOMES, *GENOTYPE-environment interaction
Abstract

The characterization of genetic risk factors for complex diseases located on chromosome-6 frequently requires human leucocyte antigen (HLA) genotyping of large patient cohorts. Currently available methods do not support high-throughput HLA typing beyond the major allele group level. We, thus, developed a high-throughput approach for the HLA-DQB1 and HLA-DRB1 loci that is based on PyrosequencingTM. PyrosequencingTM offers a higher degree of automation than direct sequencing or oligotyping. Using a dispensation order optimized for the particular HLA locus, rapid group typing and fine resolution can be achieved. We implemented the method for two important HLA loci– DQB1 and DRB1. The HLA-DQB1 typing method comprises the following steps: splitting the potential alleles after a generic polymerase chain reaction (PCR) amplification into groups with a first PyrosequencingTM reaction and resolving the split allele groups by means of five further PyrosequencingTM reactions. The HLA-DR gene family is known to be the most polymorphic one in the HLA class-II region because of a large number of DRB1 alleles. Because of this complex nature, HLA-DRB1 typing was performed by means of a combination of sequence-specific PCR typing and PyrosequencingTM. HLA-DQB1 typing and HLA-DRB1 typing were performed successfully by using standard DNA samples with the help of known HLA genotypes and in a blind study by using the samples from the Deutscher Zell Austausch 2002 and 2003. The approach was optimized and was practically tested for genotyping in disease association studies. Our well-elaborated PyrosequencingTM-based protocols offer a new alternative to the existing HLA class-II typing methods and represent a convenient and economic solution, a unique combination of high accuracy with high-sample throughput. [ABSTRACT FROM AUTHOR]

Published
2005
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15. New strategies for efficient typing of HLA class-II loci DQB1 and DRB1 by using PyrosequencingTM.

Author

Entz, P., Toliat, M.R., Hampe, J., Valentonyte, R., Jenisch, S., Nürnberg, P., and Nagy, M.

Subjects
HLA histocompatibility antigens, DISEASE risk factors, GENETIC polymorphisms, POLYMERASE chain reaction, CHROMOSOMES, GENOTYPE-environment interaction
Abstract

The characterization of genetic risk factors for complex diseases located on chromosome-6 frequently requires human leucocyte antigen (HLA) genotyping of large patient cohorts. Currently available methods do not support high-throughput HLA typing beyond the major allele group level. We, thus, developed a high-throughput approach for the HLA-DQB1 and HLA-DRB1 loci that is based on PyrosequencingTM. PyrosequencingTM offers a higher degree of automation than direct sequencing or oligotyping. Using a dispensation order optimized for the particular HLA locus, rapid group typing and fine resolution can be achieved. We implemented the method for two important HLA loci– DQB1 and DRB1. The HLA-DQB1 typing method comprises the following steps: splitting the potential alleles after a generic polymerase chain reaction (PCR) amplification into groups with a first PyrosequencingTM reaction and resolving the split allele groups by means of five further PyrosequencingTM reactions. The HLA-DR gene family is known to be the most polymorphic one in the HLA class-II region because of a large number of DRB1 alleles. Because of this complex nature, HLA-DRB1 typing was performed by means of a combination of sequence-specific PCR typing and PyrosequencingTM. HLA-DQB1 typing and HLA-DRB1 typing were performed successfully by using standard DNA samples with the help of known HLA genotypes and in a blind study by using the samples from the Deutscher Zell Austausch 2002 and 2003. The approach was optimized and was practically tested for genotyping in disease association studies. Our well-elaborated PyrosequencingTM-based protocols offer a new alternative to the existing HLA class-II typing methods and represent a convenient and economic solution, a unique combination of high accuracy with high-sample throughput. [ABSTRACT FROM AUTHOR]

Published
2005
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16. GLUT1 mutations are a rare cause of familial idiopathic generalized epilepsy

Author

Striano, P., Weber, Y.G., Toliat, M.R., Schubert, J., Leu, C., Chaimana, R., Baulac, S., Guerrero, R., LeGuern, E., Lehesjoki, A.-E., Polvi, A., Robbiano, A., Serratosa, J.M., Guerrini, R., Nürnberg, P., Sander, T., Zara, F., Lerche, H., and Marini, C.

Abstract

The idiopathic generalized epilepsies (IGE) are the most common genetically determined epilepsies. However, the underlying genes are largely unknown. We screened the SLC2A1gene, encoding the glucose transporter type 1 (GLUT1), for mutations in a group of 95 European patients with familial IGE.

Published
2012
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17. Glutamatergic gene variants impact the clinical profile of efficacy and side effects of haloperidol

Author

Thomas Sander, Hans-Jürgen Möller, Vita Dolžan, Antonio Drago, Mohammad R. Toliat, Dan Rujescu, Blanka Kores Plesničar, Ina Giegling, Martin Schäfer, Hans H. Stassen, Annette M. Hartmann, Alessandro Serretti, Giegling I., Drago A., Dolžan V., Plesnicar B.K., Schäfer M., Hartmann A.M., Sander T., Toliat M.R., Möller H.J., Stassen H.H., Rujescu D., Serretti A., University of Zurich, and Serretti, A

Subjects
2716 Genetics (clinical), Psychosis, Side effect, Genotype, medicine.medical_treatment, Slovenia, 610 Medicine & health, Pharmacology, Polymorphism, Single Nucleotide, Glutamatergic, 1311 Genetics, Extrapyramidal symptoms, SCHIZOPHRENIA, 1312 Molecular Biology, Genetics, Haloperidol, Medicine, Humans, General Pharmacology, Toxicology and Pharmaceutics, gene, Antipsychotic, Molecular Biology, Genetics (clinical), PHARMACOGENETICS, Positive and Negative Syndrome Scale, business.industry, Genetic Variation, medicine.disease, antipsychotic, 10072 Institute of Response Genetics, Haplotypes, Receptors, Glutamate, Schizophrenia, 1313 Molecular Medicine, Molecular Medicine, medicine.symptom, business, glutamatergic, medicine.drug, Antipsychotic Agents
Abstract

BACKGROUND: The glutamatergic system may be relevant to the pathophysiology of psychosis and to the effects of antipsychotic treatments.OBJECTIVES: We investigated a set of 62 SNPs located in genes coding for subunits of glutamatergic receptors (GAD1, GRIA1, GRIA3, GRIA4, GRID2, GRIK1, GRIK2, GRIK3, GRIK4, GRIN2B, GRM1 and GRM4), and the transporter of glycine (SLC6A5), as modulators of the effects of haloperidol.METHODS AND RESULTS: We studied a sample of 101 acutely ill psychotic patients. We then validated our result in two independent samples from Slovenia (n=71 and n=118) of schizophrenic patients treated with antipsychotics. We both investigated the antipsychotic effect (Positive and Negative Syndrome Scale) and motor side effect (Extrapyramidal Symptom Rating Scale) at baseline and days 3, 7, 14, 21 and 28. SLC6A5 variant (rs2298826) was found to be associated with a rapid rise of motor side effects at the beginning of the treatment (repeated measures of analysis of variance, P=0.0002), followed by a subsequent adaptation, probably dependent on haloperidol doses down titration. A specific effect was noted for dyskinetic symptoms. Haplotype analysis strengthened the relevance of SLC6A5: the C-A-C haplotype (rs1443548, rs883377, rs1945771) was found to be associated with higher Extrapyramidal symptom rating scale scores (overall P=0.01, haplotype P=0.000001). We successfully replicated this finding in the two independent samples from Slovenia.CONCLUSION: This result further stresses the relevance of the glutamatergic system in modulating the effects of haloperidol treatment, especially with regards to motor side effects.

Published
2011

18. Lack of association between 71 variations located in candidate genes and response to acute haloperidol treatment

Author

Mohammad R. Toliat, Antonio Drago, Ina Giegling, Diana De Ronchi, Hans H. Stassen, Dan Rujescu, Annette M. Hartmann, Martin Schäfer, Alessandro Serretti, Thomas Sander, Hans-Jürgen Möller, Giegling I., Drago A., Schäfer M., Hartmann A.M., Sander T., Toliat M.R., Möller H.J., De Ronchi D., Stassen H.H., Rujescu D., Serretti A., University of Zurich, and Serretti, A

Subjects
Oncology, Adult, Male, Candidate gene, medicine.medical_specialty, Psychosis, Time Factors, HALOPERIDOL, Genotype, medicine.medical_treatment, 610 Medicine & health, Pharmacology, Gene Frequency, Internal medicine, SCHIZOPHRENIA, medicine, Haloperidol, Humans, Antipsychotic, Psychiatric Status Rating Scales, Positive and Negative Syndrome Scale, PHARMACOGENETICS, business.industry, Mental Disorders, Dopamine antagonist, Genetic Variation, Middle Aged, medicine.disease, 3004 Pharmacology, 10072 Institute of Response Genetics, Schizophrenia, TOLERABILITY, Female, business, Pharmacogenetics, medicine.drug, Antipsychotic Agents, Genome-Wide Association Study
Abstract

RATIONALE: The antipsychotic pharmacological treatment effectiveness and side effects are at least partially driven by the genetic personal background.OBJECTIVES: In the present study, 71 genetic variations located in 21 candidate genes were investigated as modulators of the haloperidol efficacy and side effects in a sample of 101 acutely ill psychotic patients.METHODS: Patients were assessed at days 0, 7, 14, 21, and 28 (Positive and Negative Syndrome Scale (PANSS) test) and days 1, 3, 7, 14, 21, and 28 (UKU, BAS, and ESRS tests). Haloperidol plasma levels were measured at the same timepoints.RESULTS: None of the 71 variations were associated with response to treatment or with incidence of side effects passed a multiple testing threshold. A marginal association was detected between two haplotypes within the signal transducer and activator of transcription 4 gene and PANSS positive and dopamine beta-hydroxylase with PANSS negative scores (p = 0.004 and p = 0.008, respectively).CONCLUSIONS: In conclusion, no major association was observed between the investigated variations and the efficacy profile of haloperidol.

Published
2011

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