COMT, short for Catechol-O-Methyltransferase, is an enzyme responsible for the O-methylation of biologically active catechol-based molecules. It is involved in catecholamine metabolism, a pathway crucial for the proper functioning of the nervous system, and has been associated with several neurological disorders [4]. Its genetic variants have been the subject of extensive research, with genetic models helping to understand its role in health and disease.

COMT inhibitors have been established in the treatment of Parkinson's disease for over 20 years, considered the medication of choice for motor fluctuations [1]. The Val158Met polymorphism of COMT may influence the risk for psychopathy-related behaviors in children and adolescents, with different genotypes showing varying likelihoods of displaying such traits depending on age [2]. Genetic variants of COMT, along with DCX and FMR1, have been linked to neurodevelopmental disorders related to intellectual disability and social behavior, potentially converging at Wnt signaling, neuron migration, and axon and dendrite morphogenesis [3]. In Fragile X Syndrome, COMT expression is significantly reduced, affecting dopamine signaling [5]. Also, the COMT rs4680 polymorphism has been studied in relation to antidepressive treatment response, Parkinson's disease risk, and levodopa-induced dyskinesia in Parkinson's disease patients, with some associations found but inconsistent results across studies [6,7,8].

In conclusion, COMT is essential for catecholamine metabolism and is involved in multiple neurological and neuropsychiatric conditions. Studies using genetic models, though not specifically KO/CKO mouse models in the provided references, have shed light on its role in diseases like Parkinson's disease, psychopathy-related behaviors, and Fragile X Syndrome. Understanding COMT's function through these models may help in developing better treatment strategies for associated disorders.

References:

1. Jost, Wolfgang H, Buhmann, Carsten, Classen, Joseph, Woitalla, Dirk, Reichmann, Heinz. 2022. [Relevance of COMT inhibitors in the treatment of motor fluctuations]. In Der Nervenarzt, 93, 1035-1045. doi:10.1007/s00115-021-01237-3. https://pubmed.ncbi.nlm.nih.gov/35044481/

2. Kant, Tuana, Koyama, Emiko, Zai, Clement C, Beitchman, Joseph H, Kennedy, James L. 2022. COMT Val/Met and Psychopathic Traits in Children and Adolescents: A Systematic Review and New Evidence of a Developmental Trajectory toward Psychopathy. In International journal of molecular sciences, 23, . doi:10.3390/ijms23031782. https://pubmed.ncbi.nlm.nih.gov/35163702/

3. Delprato, Anna, Xiao, Emily, Manoj, Devika. 2022. Connecting DCX, COMT and FMR1 in social behavior and cognitive impairment. In Behavioral and brain functions : BBF, 18, 7. doi:10.1186/s12993-022-00191-7. https://pubmed.ncbi.nlm.nih.gov/35590332/

4. Cruz-Vicente, Pedro, Gonçalves, Ana M, Barroca-Ferreira, Jorge, Gallardo, Eugénia, Passarinha, Luis A. 2022. Unveiling the biopathway for the design of novel COMT inhibitors. In Drug discovery today, 27, 103328. doi:10.1016/j.drudis.2022.07.013. https://pubmed.ncbi.nlm.nih.gov/35907613/

5. Utami, Kagistia Hana, Yusof, Nur Amirah Binte Muhammed, Garcia-Miralles, Marta, Langley, Sarah R, Pouladi, Mahmoud A. 2023. Dysregulated COMT Expression in Fragile X Syndrome. In Neuromolecular medicine, 25, 644-649. doi:10.1007/s12017-023-08754-1. https://pubmed.ncbi.nlm.nih.gov/37684514/

6. Tang, Zhen, Zhang, Shumin, Guo, Dongmei, Wang, Hanyan. 2020. Association between COMT gene Val108/158Met and antidepressive treatment response: A meta-analysis. In Gene, 734, 144333. doi:10.1016/j.gene.2020.144333. https://pubmed.ncbi.nlm.nih.gov/31972309/

7. Jiménez-Jiménez, Félix J, Alonso-Navarro, Hortensia, García-Martín, Elena, Agúndez, José A G. . COMT gene and risk for Parkinson's disease: a systematic review and meta-analysis. In Pharmacogenetics and genomics, 24, 331-9. doi:10.1097/FPC.0000000000000056. https://pubmed.ncbi.nlm.nih.gov/24819480/

8. Yin, Yanying, Liu, Yang, Xu, Meisong, Zhang, XiaoMin, Li, Chen. 2021. Association of COMT rs4680 and MAO-B rs1799836 polymorphisms with levodopa-induced dyskinesia in Parkinson's disease-a meta-analysis. In Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology, 42, 4085-4094. doi:10.1007/s10072-021-05509-3. https://pubmed.ncbi.nlm.nih.gov/34346015/