Association of Codon 108/158 Catechol-O-Methyltransferase Gene Polymorphism with the Psychiatric Manifestations of Velo-Cardio-Facial Syndrome

Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
American Journal of Medical Genetics (Impact Factor: 3.23). 09/1996; 67(5):468-72. DOI: 10.1002/(SICI)1096-8628(19960920)67:5<468::AID-AJMG5>3.0.CO;2-G
Source: PubMed

ABSTRACT Velo-cardio-facial-syndrome (VCFS) is a common congenital disorder associated with typical facial appearance, cleft palate, cardiac defects, and learning disabilities. The majority of patients have an interstitial deletion on chromosome 22q11. In addition to physical abnormalities, a variety of psychiatric illnesses have been reported in patients with VCFS, including schizophrenia, bipolar disorder, and attention deficit hyperactivity disorder. The psychiatric manifestations of VCFS could be due to haploin-sufficiency of a gene(s) within 22q11. One candidate that has been mapped to this region is catechol-O-methyltransferase (COMT). We recently identified a polymorphism in the COMT gene that leads to a valine-->methionine substitution at amino acid 158 of the membrane-bound form of the enzyme. Homozygosity for COMT158met leads to a 3-4-fold reduction in enzymatic activity, compared with homozygotes for COMT158val. We now report that in a population of patients with VCFS, there is an apparent association between the low-activity allele, COMT158met, and the development of bipolar spectrum disorder, and in particular, a rapid-cycling form.

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Available from: Gianni L Faedda, Jul 26, 2015
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    • "We focused on this single nucleotide polymorphism, as it is the most established and widely studied functional mutation in the COMT gene (Chen et al. 2004; Scheggia et al. 2012). Future investigations with larger samples size would be required to assess the potential effects played by other COMT functional polymorphisms/ haplotypes (Lachman et al. 1996; Bray et al. 2003; Meyer-Lindenberg et al. 2006; Nackley et al. 2006; Gothelf et al. 2014). Written, informed consent was obtained from all subjects participating in the study, which was approved by the local ethics committee at the Santa Lucia Foundation of Rome. "
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    • "The COMT gene, mapped to chromosome 22q11, encodes catechol- O-methyltransferase, the enzyme that catalyzes the degradation of catecholamines and the methylation of catechol estrogens, an important mechanism for inactivating estrogen [10]. The COMT gene exhibits a functional single nucleotide polymorphism (SNP) (rs4680) due to a G to A transition that results in an amino acid change from valine to methionine at codon 158 (Val158Met) [11]. A different COMT activity is associated with this polymorphism, since the enzyme activity of the Met/ Met genotype is one quarter of that observed in the Val/Val genotype, and heterozygous subjects exhibit intermediate enzyme activity [12]. "
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    ABSTRACT: The greater predisposition of women to Alzheimer's disease (AD), owing to the decrease in postmenopausal estrogen, may be influenced by polymorphic variation in genes regulating estrogen metabolism (e.g., COMT) and estrogen biosynthesis (e.g., CYP17). In order to better understand how the estrogen pathway genetic variation might affect AD onset, we conducted a case-control study of two single nucleotide polymorphisms (SNPs) of these two genes (COMT rs4680 and CYP17 rs743572) in a sample of AD patients of Italian origin. The COMT allele and genotype were found associated neither with AD onset nor with parameters of AD severity, such as cognitive impairment, age at onset, or disease duration. In contrast, CYP17 was found to affect the age at disease onset mainly in males and, as compared with noncarriers, people carrying the A2 (C) allele had a 2.2-fold increased risk for AD. These findings suggest that the CYP17 A2 allele influences AD susceptibility in a sex-specific way by acting not only on AD risk but also on the age at disease onset, an important parameter of AD severity.
    Journal of the Neurological Sciences 06/2014; 344(1-2). DOI:10.1016/j.jns.2014.06.045
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    • "An SNP occurring at COMT gene codon 158 results in a G 0A valine (val) to methionine (met) substitution that occurs relatively frequently. The val allele manifests as higher COMT activity and reduced synaptic dopamine availability, whereas the met allele manifests as reduced COMT activity and increased synaptic dopamine availability (Lachman, Papolos, et al., 1996). The val158met polymorphism has been the subject of strong research interest and a variety of studies have uncovered promising findings. "
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    ABSTRACT: Introduction. Bipolar Disorder (BD) is a serious mood disorder, the aetiology of which is still unclear. The disorder is characterised by extreme mood variability in which patients fluctuate between markedly euphoric, irritable, and elevated states to periods of severe depression. The current research literature shows that BD patients demonstrate compromised neurocognitive ability in addition to these mood symptoms. Viable candidate genes implicated in neurocognitive and socioemotional processes may explain the development of these core emotion abnormalities. Additionally, links between faulty neurocognition and impaired socioemotional ability complement genetic explanations of BD pathogenesis. This review examines associations between cognition indexing prefrontal neural regions and socioemotional impairments including emotion processing and regulation. A review of the effect of COMT and TPH2 on these functions is also explored. Methods. Major computer databases including PsycINFO, Google Scholar, and Medline were consulted in order to conduct a comprehensive review of the genetic and cognitive literature in BD. Results. This review determines that COMT and TPH2 genetic variants contribute susceptibility to abnormal prefrontal neurocognitive function which oversees the processing and regulation of emotion. This provides for greater understanding of some of the emotional and cognitive symptoms in BD. Conclusions. Current findings in this direction show promise, although the literature is still in its infancy and further empirical research is required to investigate these links explicitly.
    Cognitive Neuropsychiatry 10/2012; DOI:10.1080/13546805.2012.690938
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