Neurobiology of a Mutation in Glycine Metabolism in Psychotic Disorders

描述（由申请人提供）：最近的研究结果表明，复杂精神疾病中相当大比例的遗传变异可以通过一系列个体罕见的、高度渗透的遗传变异来解释。这些拷贝数变异（cnv）中的每一个都可能是疾病的危险因素，并且许多是非复发性和散发的。最理想的情况是，特定突变的识别将导致针对突变的潜在生物学量身定制的个性化治疗干预。我们在9p24.1位点发现了一个复杂的结构重排，它与一个家族的精神病相分离。重排区域中的一个基因甘氨酸脱羧酶（GLDC）参与神经胶质细胞中甘氨酸的降解，并在突变携带者中复制三倍。甘氨酸是n -甲基- d -天冬氨酸受体（NMDAR）的协同激动剂。GLDC三复制的携带者可能具有低水平的脑甘氨酸，导致nmdar介导的功能减退，这与精神分裂症的病理生理学密切相关。这种突变的携带者是强有力的候选人受益于甘氨酸增加他们的精神药物方案。这项R21申请的目的之一是在该突变携带者中开展一项原理验证的双盲安慰剂对照甘氨酸增强试验，并评估临床症状和神经认知功能的变化。我们还建议对同一家族的突变携带者和非携带者进行有针对性的神经生物学随访，以表征该突变的大脑结构、功能和神经化学特性。这些研究将利用质子磁共振波谱法探测甘氨酸稳态，评估急性口服甘氨酸后脑和血浆甘氨酸水平之间的关系，并检查与nmda介导的神经传递失调有关的脑通路（大细胞）。相同的程序（除了甘氨酸加载扫描）将在开放标签甘氨酸增加六周后重新给药。该结果将显著增强我们对与精神病相关的罕见CNVs的神经生物学及其与疾病病理生理学的相关性的理解。更重要的是，该结果将首次将病理生理学和医学上可行的治疗干预与潜在的遗传学联系起来，这对其他神经精神疾病患者有潜在的好处，这些患者在相同的基因或其他基因/途径中发生突变，受到相同或相关的异常生物过程的影响。

DESCRIPTION (provided by applicant): Recent findings suggest that a significant proportion of the genetic variance in complex psychiatric disorders can be explained by a collection of individually rare, highly penetrant genetic variants. Each of these copy number variants (CNVs) may be a risk factor for disease, and many are non-recurrent and sporadic. Optimally, the identification of specific mutations would result in personalized treatment interventions tailored to the underlying biology of the mutation. We have identified a complex structural rearrangement at 9p24.1 that segregates with psychosis in one family. One gene in the rearranged region, glycine decarboxylase (GLDC), is involved in the degradation of glycine in glia cells and is triplicated in mutation carriers. Glycine is a co-agonist for the N-methyl-D-aspartate receptor (NMDAR). Carriers of the GLDC triplication would be expected to have low levels of brain glycine, resulting in NMDAR-mediated hypofunction, which has been strongly implicated in the pathophysiology of schizophrenia. The carriers of this mutation are strong candidates to benefit from glycine augmentation of their psychotropic drug regimens. One aim of this R21 application is to carry out a proof-of-principle double-blind placebo-controlled glycin augmentation trial in carriers of this mutation and to assess changes in clinical symptoms and neurocognitive function. We also propose to carry out targeted neurobiological follow-up of mutation carriers and non-carriers in the same family in order to characterize the brain structural, functional and neurochemical properties of this mutation. These studies will probe glycine homeostasis using proton magnetic resonance spectroscopy, assess the relationship between brain and plasma glycine levels following an acute oral dose of glycine, and examine brain pathways (magnocellular) implicated in dysregulation of NMDA-mediated neurotransmission. The same procedures (except for the glycine loading scans) will be re-administered to carriers after six weeks of open label glycine augmentation. The results will significantly enhance our understanding of the neurobiology of rare CNVs associated with psychosis and their relevance to disease pathophysiology. More importantly, the results will, for the first time, link pathophysiology and a medically actionable treatment intervention to underlying genetics, with potential benefit to other patients with neuropsychiatric disease who have mutations in either the same gene or in other genes/pathways that are impacted by the same or related aberrant biological processes.