Understanding the Role of COMT Variants in Sensorimotor Gating

描述（由申请人提供）：在人类儿茶酚-o-甲基转移酶（COMT）基因中存在一个单核苷酸多态性（SNP），导致编码区密码子158缬氨酸到蛋氨酸的错义突变（称为val158met）。这种COMT- met多态性在人类中是独一无二的，它会使前额皮质组织中的COMT酶活性降低40%。这种酶活性的降低可以减少大脑皮层的多巴胺清除率，增强多巴胺信号。由于有证据支持精神分裂症患者前额皮质多巴胺信号减少，COMT基因与精神分裂症之间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是不一致的，并且只支持一小部分贡献。考虑到大多数神经精神疾病的复杂性和重叠性，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，神经精神功能或“内表型”的最佳减少测量可能比诊断更有用，以了解精神分裂症等精神疾病的遗传贡献。初步数据表明，在小鼠和人类中，预脉冲抑制是由COMT基因调节的。脉冲前抑制是一种可操作的感觉运动门控措施，在精神分裂症中是缺乏的。关于COMT val158met对这种和其他精神分裂症内表型影响的功能机制知之甚少。COMT SNP是一个编码区SNP，在多巴胺代谢途径中具有很好的功能作用，在人和小鼠之间相对保守，因此非常适合在小鼠中建模。事实上，“表达小鼠感兴趣的特定人类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：含有人类等位基因的小鼠模型：研究大脑功能的新工具）。为了响应这一项目公告，将创建两个突变小鼠系，每个系携带一个人类COMT基因，具有缬氨酸或蛋氨酸多态性。研究将验证一种假设，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，会表现出较差的脉冲前抑制性能。COMT val158met多态性的小鼠模型可能在确定COMT对感觉运动门控等神经精神内表型的影响机制方面发挥关键作用。在未来，该模型可以帮助检查COMT基因易感性与精神分裂症和其他神经精神疾病（如压力、免疫挑战和发育侮辱）相关的其他基因或环境因素的相互作用。

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.