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catechol-o-methyltransferase and schizophrenia

Christian Lerner, Roland Jakob-Roetne, Bernd Buettelmann, Andreas Ehler, Markus Rudolph, Rosa María Rodríguez Sarmiento
A fragment screening approach designed to target specifically the S-adenosyl-l-methionine pocket of catechol O-methyl transferase allowed the identification of structurally related fragments of high ligand efficiency and with activity on the described orthogonal assays. By use of a reliable enzymatic assay together with X-ray crystallography as guidance, a series of fragment modifications revealed an SAR and, after several expansions, potent lead compounds could be obtained. For the first time nonphenolic and small low nanomolar potent, SAM competitive COMT inhibitors are reported...
October 14, 2016: Journal of Medicinal Chemistry
C L Clelland, V Drouet, K C Rilett, J A Smeed, R H Nadrich, A Rajparia, L L Read, J D Clelland
Elevated peripheral proline is associated with psychiatric disorders, and there is evidence that proline is a neuromodulator. The proline dehydrogenase (PRODH) gene, which encodes the enzyme that catalyzes proline catabolism, maps to human chromosome 22q11.2, a region conferring risk of schizophrenia. In the Prodh-null mouse, an interaction between elevated peripheral proline and another 22q11.2 gene, catechol-O-methyltransferase (COMT), on neurotransmission and behavior has been reported. We explored the relationship between fasting plasma proline levels and COMT Val(158)Met genotype on symptoms (positive, negative and total) in schizophrenia patients...
2016: Translational Psychiatry
Livia Casarelli, Maurizio Minnei, Mariabernarda Pitzianti, Marco Armando, Maria Pontillo, Stefano Vicari, Augusto Pasini
22q11 Deletion syndrome (22q11DS) is a neurogenetic disorder, resulting from a hemizygous microdeletion on the long arm of chromosome 22. In 22q11DS, the phenotypic expression is highly variable. Approximately one-third of all individuals with 22q11DS develop schizophrenia-like psychotic disorder. Among the genes in the deleted region, catechol-O-methyltransferase (COMT) has a particular relevance for psychiatric disorders: lower COMT enzymatic activity decreases the clearance of dopamine (DA), yielding higher levels of catecholamines in the central nervous system...
October 2016: Psychiatric Genetics
Marco Bortolato, Consuelo Walss-Bass, Peter M Thompson, Jackob Moskovitz
OBJECTIVES: The enzyme catechol-O-methyltransferase (COMT), which catalyses the degradation of dopamine and norepinephrine, is posited to participate in the pathophysiology of bipolar disorder (BD) and schizophrenia. In support of this notion, rich evidence has documented that the severity of various BD and schizophrenia symptoms is moderated by rs4680, a single nucleotide polymorphism of the COMT gene featuring a valine (Val)-to-methionine (Met) substitution that results in lower catalytic activity...
July 26, 2016: World Journal of Biological Psychiatry
Pilar Lopez-Garcia, Alexandra Cristobal-Huerta, Leslie Young Espinoza, Patricio Molero, Felipe Ortuño Sanchez-Pedreño, Juan Antonio Hernández-Tamames
UNLABELLED: Context processing deficits have been shown to be present in chronic and first episode schizophrenia patients and in their relatives. This cognitive process is linked to frontal functioning and is highly dependent on dopamine levels in the prefrontal cortex (PFC). The catechol-O-methyltransferase (COMT) enzyme plays a prominent role in regulating dopamine levels in PFC. Genotypic variations in the functional polymorphism Val(158)Met COMT appear to have an impact in dopamine signaling in the PFC of healthy subjects and schizophrenia patients...
November 3, 2016: Progress in Neuro-psychopharmacology & Biological Psychiatry
Qiao Mao, Yun-Long Tan, Xing-Guang Luo, Li Tian, Zhi-Ren Wang, Shu-Ping Tan, Song Chen, Gui-Gang Yang, Hui-Mei An, Fu-De Yang, Xiang-Yang Zhang
Catechol-O-methyltransferase (COMT), an enzyme involved in the degradation and inactivation of the neurotransmitter dopamine, is associated with the sensory gating phenomenon, protecting the cerebral cortex from information overload. The COMT Val(108/158)Met polymorphism is essential for prefrontal cortex processing capacity and efficiency. The current study was designed to investigate the role of COMT Val(108/158)Met polymorphism in development, sensory gating deficit, and symptoms of schizophrenia in Han Chinese population...
August 30, 2016: Psychiatry Research
Cathy K Wang, Ana Aleksic, Michael S Xu, Ric M Procyshyn, Colin J Ross, Fidel Vila-Rodriguez, Alfredo Ramos-Miguel, Ryan Yan, William G Honer, Alasdair M Barr
AIMS: Catechol-O-methyltransferase (COMT) is an enzyme involved in the degradation of catecholamine neurotransmitters. Due to its role in neurotransmitter flux, multiple COMT variants have been associated with the development of psychiatric disorders. Notably, select single-nucleotide polymorphisms (SNPs) of the COMT gene have been implicated in schizophrenia risk, severity, and treatment response. In recognition of the value of a streamlined genotyping method for COMT SNP detection, this study was designed to develop a simple and economical tetra-primer amplification refractory mutation system (T-ARMS) assay for the concurrent detection of eight COMT SNPs: rs4680, rs737865, rs165599, rs2075507, rs4633, rs4818, rs6269, and rs165774...
August 2016: Genetic Testing and Molecular Biomarkers
Abhay A Shukla, Manish Jha, Thomas Birchfield, Shibani Mukherjee, Kelly Gleason, Salim Abdisalaam, Aroumougame Asaithamby, Beverley Adams-Huet, Carol A Tamminga, Subroto Ghose
The single nucleotide val158met polymorphism in catechol o-methyltransferase (COMT) influences prefrontal cortex function. Working memory, dependent on the dorsolateral prefrontal cortex (DLPFC), has been repeatedly shown to be influenced by this COMT polymorphism. The high activity COMT val isoform is associated with lower synaptic dopamine levels. Altered synaptic dopamine levels are expected to lead to molecular adaptations within the synapse and within DLPFC neural circuitry. In this human post mortem study using high quality DLPFC tissue, we first examined the influence of the COMT val158met polymorphism on markers of dopamine neurotransmission, N-methyl-d-aspartate (NMDA) receptor subunits and glutamatic acid decarboxylase 67 (GAD67), all known to be critical to DLPFC circuitry and function...
May 2016: Schizophrenia Research
Thelma Beatriz González-Castro, Yazmin Hernández-Díaz, Isela Esther Juárez-Rojop, María Lilia López-Narváez, Carlos Alfonso Tovilla-Zárate, Ana Fresan
An association between a catechol-O-methyltransferase (COMT) Val156Met (rs4680) polymorphism and schizophrenia has been reported in the literature, although no conclusive outcomes have been attained. The aim of this study was to evaluate the association of the COMT Val108/158Met polymorphism with schizophrenia in a systematic review and meta-analysis. We performed a keyword search on PubMed and EBSCO databases. All English language case-control studies published up to April 2015 were selected. A total of 67 studies were selected for inclusion...
June 2016: Neuromolecular Medicine
Brian Dean, Elizabeth Scarr
Catechol-O-methyltransferase (COMT) genotype has been associated with varying levels of cognitive functioning and an altered risk of schizophrenia. COMT regulates the breakdown of catecholamines, particularly dopamine, which is thought critical in maintaining cognitive function and the aetiology of schizophrenia. This hypothesis gained support from reports that the VAL allele at rs4680 was associated with poorer performance on cognitive tests and a slightly increased risk of schizophrenia. More recently, genotype at rs4818, part of a hapblock with rs4680, has been shown to impact on cognitive ability more than genotype at rs4680 but, as yet, not the risk for schizophrenia...
September 2016: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
Petya D Radoeva, Wanda Fremont, Kevin M Antshel, Wendy R Kates
Velocardiofacial syndrome, also known as 22q11.2 deletion syndrome (22q11DS), is associated with an increased risk of major psychiatric disorders, including schizophrenia. The emergence of psychotic symptoms in individuals with schizophrenia in the general population is often preceded by a premorbid period of poor or worsening social and/or academic functioning. Our current study evaluated premorbid adjustment (via the Cannon-Spoor Premorbid Adjustment Scale [PAS]) and psychotic symptoms (via the Structured Interview for Prodromal Symptoms and the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version) in youth with 22q11DS (N = 96), unaffected siblings (N = 40), and community controls (N = 50)...
February 11, 2016: Development and Psychopathology
Ryoko Higashiyama, Tohru Ohnuma, Yuto Takebayashi, Ryo Hanzawa, Nobuto Shibata, Hidenaga Yamamori, Yuka Yasuda, Itaru Kushima, Branko Aleksic, Kenji Kondo, Masashi Ikeda, Ryota Hashimoto, Nakao Iwata, Norio Ozaki, Heii Arai
Chromosome 22q11.2 deletion syndrome and genetic variations including single-nucleotide polymorphism (SNP) and copy number variation (CNV) in catechol-O-methyltransferase (COMT) situated at 22q11.2 remains controversial. Here, the genetic relationship between COMT and Japanese patients with schizophrenia was investigated by examining whether the SNPs correlated with schizophrenia based on a common disease-common variant hypothesis. Additionally, 22q11.2DS were screened based on a common disease-rare variant hypothesis; low-frequency CNVs situated at two COMT promoters and exons were investigated based on the low-frequency variants with an intermediate effect; and positive findings from the first stage were reconfirmed using a second-stage replication study including a larger sample size...
April 2016: American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics
Nina Teroganova, Leah Girshkin, Catherine M Suter, Melissa J Green
BACKGROUND: Increasing evidence suggests the involvement of epigenetic processes in the development of schizophrenia and bipolar disorder, and recent reviews have focused on findings in post-mortem brain tissue. A systematic review was conducted to synthesise and evaluate the quality of available evidence for epigenetic modifications (specifically DNA methylation) in peripheral blood and saliva samples of schizophrenia and bipolar disorder patients in comparison to healthy controls. METHODS: Original research articles using humans were identified using electronic databases...
2016: BMC Genetics
Eric Huang, Clement C Zai, Amanda Lisoway, Malgorzata Maciukiewicz, Daniel Felsky, Arun K Tiwari, Jeffrey R Bishop, Masashi Ikeda, Patricio Molero, Felipe Ortuno, Stefano Porcelli, Jerzy Samochowiec, Pawel Mierzejewski, Shugui Gao, Benedicto Crespo-Facorro, José M Pelayo-Terán, Harpreet Kaur, Ritushree Kukreti, Herbert Y Meltzer, Jeffrey A Lieberman, Steven G Potkin, Daniel J Müller, James L Kennedy
BACKGROUND: The catechol-O-methyltransferase (COMT) enzyme plays a crucial role in dopamine degradation, and the COMT Val158Met polymorphism (rs4680) is associated with significant differences in enzymatic activity and consequently dopamine concentrations in the prefrontal cortex. Multiple studies have analyzed the COMT Val158Met variant in relation to antipsychotic response. Here, we conducted a meta-analysis examining the relationship between COMT Val158Met and antipsychotic response...
May 2016: International Journal of Neuropsychopharmacology
Francesco Papaleo, Sara Sannino, Fabrizio Piras, Gianfranco Spalletta
Different genetic variations in the catechol-O-methyltransferase (COMT) gene have been indicated to functionally regulate the encoded enzyme. Despite the vast literature on the single nucleotide COMT ValMet polymorphism, the impact of complex haplotypes on cognitive functions has been overlooked. Here we contrasted the effects of complex COMT haplotypes with the ValMet polymorphism on cognitive functions and their interaction with menopause, in healthy subjects and patients with schizophrenia. Healthy adults (N=229) as well as patients with schizophrenia (N=172) underwent a comprehensive cognitive assessment taking into account the menopausal state...
December 2015: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
Jean-Pierre Lindenmayer, Anzalee Khan, Herbert Lachman, Susan R McGurk, Abraham Goldring, Amod Thanju, Saurabh Kaushik
BACKGROUND: A functional polymorphism of the catechol-O-methyltransferase (COMT) gene (Val158Met) partially appears to influence cognitive performance in schizophrenia subjects and healthy controls by modulating prefrontal dopaminergic activity. This study evaluated the association of the COMT Val108/158 Met genotype with response to computerized neurocognitive remediation (CRT). METHOD: 145 subjects with DSM-IV-TR schizophrenia or schizoaffective disorder were genotyped via saliva sampling...
October 2015: Schizophrenia Research
Augusto Q Pedro, Luís M Martins, João M L Dias, Maria J Bonifácio, João A Queiroz, Luís A Passarinha
BACKGROUND: Membrane proteins are important drug targets in many human diseases and gathering structural information regarding these proteins encourages the pharmaceutical industry to develop new molecules using structure-based drug design studies. Specifically, membrane-bound catechol-O-methyltransferase (MBCOMT) is an integral membrane protein that catalyzes the methylation of catechol substrates and has been linked to several diseases such as Parkinson's disease and Schizophrenia. Thereby, improvements in the clinical outcome of the therapy to these diseases may come from structure-based drug design where reaching MBCOMT samples in milligram quantities are crucial for acquiring structural information regarding this target protein...
2015: Microbial Cell Factories
Anupa A Vijayakumari, John P John, Harsha N Halahalli, Pradip Paul, Priyadarshini Thirunavukkarasu, Meera Purushottam, Sanjeev Jain
OBJECTIVE: We examined the effect of risk alleles of polymorphisms of three schizophrenia risk genes that mediate monoamine signalling in the brain on regional brain volumes of schizophrenia and healthy control subjects. The risk alleles and the gene polymorphisms studied were: Val allele of catechol o-methyltransferase (COMT) rs4680 polymorphism; short allele of 5-hydroxy tryptamine transporter linked polymorphic region (5HTTLPR) polymorphism; and T allele of 5-hydroxy tryptamine 2A (5HT2A) rs6314 polymorphism...
April 30, 2015: Clinical Psychopharmacology and Neuroscience: the Official Scientific Journal of the Korean College of Neuropsychopharmacology
Yinfei Li, Wei Deng, Qiang Wang, Mingli Li, Na Li, Wei Lei, Zhe Li, Xiaohong Ma, Xiehe Liu, Tao Li
OBJECTIVE: To assess the association of impairment of surface area of first-episode schizophrenia(SZ) with polymorphisms of COMT gene, and the difference in the impaired patterns between familial patients with schizophrenia(FPS) and sporadic patients with schizophrenia(SPS). METHODS: Ninety-eight patients with first-episode SZ(FPS=40, SPS=58) and 78 healthy controls were recruited. COMT gene was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method...
April 2015: Zhonghua Yi Xue Yi Chuan Xue za Zhi, Zhonghua Yixue Yichuanxue Zazhi, Chinese Journal of Medical Genetics
Rukhsana Nawaz, Sonia Siddiqui
Schizophrenia is a neuropsychiatric disorder in which abnormalities in the prefrontal cortex lead to impaired synthesis of dopamine. It is associated with hallucination, psychosis and hearing impairments. Many susceptible genes have been identified in schizophrenia such as catechol-O-methyltransferase (COMT) and serine/threonine kinase (AKT1). Single nucleotide polymorphisms (SNPs) in these genes have not been identified in Pakistan. Therefore, we investigated the allelic and genotypic frequencies in COMT and AKT1 genes in the Pakistani population...
2015: CNS & Neurological Disorders Drug Targets
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