Understanding the Role of COMT Variants in Sensorimotor Gating

描述(申请人提供)：在人类儿茶酚-O-甲基转移酶(COMT)基因中存在单核苷酸多态(SNP)，导致编码区158密码子Valine错义突变为蛋氨酸(称为val158met)。这种COMT-Met多态对人类来说是独一无二的，它会使前额叶皮质组织中的COMT酶活性降低40%。这种酶活性的下降可以减少皮质中的多巴胺清除，并增强多巴胺信号。由于证据支持精神分裂症患者前额叶皮质多巴胺信号的减少，COMT基因与精神分裂症的关系已被广泛研究。然而，COMT val158Met SNP与精神分裂症风险的关联研究并不一致，只支持一小部分贡献。考虑到大多数神经精神障碍的复杂性和重叠性质，不太可能确定一个简单的基因到复杂的特征机制。相反，有人建议，减少神经精神功能或“内表型”的最佳测量可能比诊断更有用，以了解基因对精神分裂症等精神疾病的贡献。初步数据表明，在小鼠和人类中，前脉冲抑制都受到COMT基因的调节。脉冲前抑制是精神分裂症患者缺乏的感觉运动门控的可操作性措施。关于COMT val158met对这种和其他精神分裂症内表型的作用机制，人们知之甚少。COMT SNP是一个编码区，对人类和小鼠之间相对保守的多巴胺代谢途径具有很好的功能影响，因此非常适合于小鼠建模。事实上，“在小鼠身上表达特定的人类感兴趣的等位基因可能有助于阐明基因/蛋白质的调节和功能，为研究与大脑发育、生理学、药理学、神经化学和行为相关的人类基因提供新的模型系统”(RFA NH08-050：小鼠模型包含人类等位基因：研究脑功能的新工具)。作为对这一计划宣布的回应，将创建两个突变小鼠品系，每个品系都携带具有Valine或蛋氨酸多态的人类COMT基因。研究将检验这一假设，即与人类相似，携带COMT-Val等位基因的小鼠与携带COMT-Met等位基因的小鼠相比，将表现出较差的脉冲前抑制性能。这种COMT val158met多态的小鼠模型可以在鉴定COMT对神经精神内表型(如感觉运动门控)的影响机制方面发挥关键作用。在未来，这个模型可以帮助检查COMT基因易损性与其他与精神分裂症和其他神经精神障碍相关的基因或环境因素的相互作用，如应激、免疫挑战和发育侮辱。

DESCRIPTION (provided by applicant): A single nucleotide polymorphism (SNP), causing a missense mutation of codon 158 Valine to Methionine in the coding region (termed val158met), exists in the human catechol-o-methyltransferase (COMT) gene. This COMT-Met polymorphism is unique for humans and decreases COMT enzymatic activity 40% in prefrontal cortex tissue. This decrease in enzymatic activity can reduce dopamine clearance in the cortex and enhance dopamine signaling. Since evidence supports a reduction in dopamine signaling in prefrontal cortex in schizophrenia patients, the relationship between the COMT gene and schizophrenia has been extensively studied. Association studies of the COMT val158met SNP with schizophrenia risk are inconsistent, however, and support only a small contribution. Given the complexity and overlapping nature of most neuropsychiatric disorders, it is unlikely that a simple gene to complex trait mechanisms can be identified. Instead, it has been suggested that optimally reduced measures of neuropsychiatric function or "endophenotypes" may be more useful than diagnoses to understand genetic contributions to psychiatric disorders such as schizophrenia. Preliminary data indicate that prepulse inhibition is modulated by the COMT gene in both mice and humans. Prepulse inhibition is an operational measure of sensorimotor gating that is deficient in schizophrenia. Little is known about the functional mechanisms underlying COMT val158met effects on this and other schizophrenia endophenotypes. The COMT SNP is ideally suited for modeling in mice as it is a coding region SNP with a well characterized functional effect on the dopamine metabolism pathway, which is relatively conserved between humans and mice. Indeed, "expressing specific human alleles of interest in mice may help elucidate gene/protein regulation and function, providing novel model systems to study human genes related to brain development, physiology, pharmacology, neurochemistry, and behavior" (RFA NH08-050: Mouse Models Containing Human Alleles: Novel Tools to Study Brain Function). In response to this program announcement, two mutant mouse lines will be created, each carrying a human COMT gene with either the Valine or Methionine polymorphism. Studies will test the hypothesis that similar to humans, mice carrying the COMT-Val allele will show poor prepulse inhibition performance compared to mice carrying the COMT-Met allele. This mouse model of COMT val158met polymorphism could play a critical role in the identification of mechanisms of COMT effects on neuropsychiatric endophenotypes such as sensorimotor gating. In the future, this model can aid in examination of COMT gene vulnerability interactions with other genes or environmental factors relevant to schizophrenia and other neuropsychiatric disorders, such as stress, immune challenge, and developmental insult.