Biopterin Deficit in Schizophrenia: Genetic Dissection of BH4 Biosynthesis.

描述（由申请人提供）：四氢生物蝶呤（BH4）是维持胺类神经递质的可用性的重要辅助因子，包括多巴胺和血清素，调节一氧化氮的合成，刺激和调节谷氨酸系统。神经递质（NT）系统的失调与精神分裂症（SZ）的发病机制有关。基于BH4在NT合成中的核心作用，我们在大量SZ患者和对照组中检测了血浆总生物蝶呤水平（BH4的测量值）。与对照组相比，SZ患者组的平均生物蝶呤缺陷非常显著，为34%。观察到的生物蝶呤缺陷与报道的遗传性BH4缺乏性疾病相当，支持其具有生理意义的表征。我们非常重要的发现，以及：a) BH4在NT维持中的已知作用，b)在人和小鼠BH4缺乏中观察到的CNS NT合成失调，c)血浆生物蝶呤水平与CNS生物蝶呤水平相关的证据，以及d)尿生物蝶呤排泄在SZ中没有增加的证据，都支持了我们的假设，即BH4生物合成失调与SZ的发病有关。SZ易感性具有很大的遗传成分，在另一项初步研究中，我们对BH4生物合成途径的第一个基因GCH1进行了初步基因检测，在132名受试者（86名SZ和46名对照）中分型出与SZ相关的多态性。结果令人震惊：我们发现GCH1与SZ密切相关：比值比为5.0,p= 0.0057。我们还发现GCH1等位基因状态可以预测SZ患者的低生物蝶呤水平。基于这些非常积极的初步数据，并考虑到部分没有SZ相关GCH1基因型的SZ受试者也存在生物蝶呤缺陷，本探索性研究旨在验证GCH1和其他BH4生物合成相关基因的DNA变异与生物蝶呤水平相关并影响生物蝶呤水平，是SZ候选易感位点的假设。我们将采用重测序阵列来筛选可能影响基因表达和/或蛋白质功能的DNA变异。本研究中产生的序列数据将分析与低生物蝶呤水平和受试者诊断的关系。本研究的具体目的是：目的1a。设计重新测序阵列，包括6个BH4生物合成途径基因的基因调控区、内含子-外显子边界和编码区，以及13个BH4调控相关基因。1 b。生成180名受试者（90名SZ受试者和90名对照组）的基因序列数据，所有受试者均检测血浆生物蝶呤水平。目标2。利用单标记关联检测和单倍型分析对序列数据进行分析，确定与SZ和生物蝶蛋白缺陷相关的DNA变异。了解SZ生物蝶呤缺陷的遗传基础将是开发药物的首要任务，也可能允许症状前和早期诊断测试，以及早期治疗，这可能会改善SZ高危人群的临床结果。7. 项目描述：这项研究将测试精神分裂症患者（SZ）是否在产生BH4的基因中也有DNA异常，这些人体内一种对大脑功能非常重要的化学物质BH4水平异常低。如果确实如此，我们将寻找治疗低BH4水平的方法，并尝试通过这种方式改善患者的症状。我们也可以预测患有这种基因缺陷的人患SZ的风险，因此可能能够尽早开始治疗，以改善患有这种疾病的人和有患SZ风险的年轻人的预后。

DESCRIPTION (provided by applicant): Tetrahydrobiopterin (BH4) is a vital cofactor that maintains availability of amine neurotransmitters including Dopamine and Serotonin, regulates Nitric Oxide synthesis, and stimulates and modulates the Glutamatergic system. Dysregulation of neurotransmitter (NT) systems has been implicated in the pathogenesis of schizophrenia (SZ). Based on the central roles of BH4 in NT synthesis, we assayed plasma total biopterin levels (a measure of BH4) in a large sample of patients with SZ and control subjects. A highly significant mean biopterin deficit of 34% was observed for the SZ patient group when compared to controls. The observed biopterin deficit is comparable to that reported for genetic BH4 deficiency disorders, supporting its characterization as having physiological significance. Our highly significant finding, along with: a) the known roles of BH4 in NT maintenance, b) dysregulation of CNS NT synthesis observed in human and mouse BH4 deficiencies, c) evidence that plasma biopterin levels are correlated with CNS biopterin levels, and d) evidence that urinary biopterin excretion is not increased in SZ, all support our hypothesis that dysregulation of BH4 biosynthesis is involved in the etiology of SZ. SZ susceptibility has a large genetic component, and in another preliminary study, we have performed initial genetic testing of GCH1, the first gene in the BH4 biosynthesis pathway, genotyping a polymorphism for association with SZ in a sample of 132 subjects (86 SZ and 46 control subjects). The results were striking: We found that GCH1 was strongly associated with SZ: odds ratio, 5.0, p= 0.0057. We also found that GCH1 allele status predicts low biopterin in SZ patients. Based on these very positive preliminary data, and the fact that some SZ subjects without the SZ-associated GCH1 genotype also have a biopterin deficit, this exploratory study is designed to test the hypothesis that DNA variants in GCH1 and other BH4 biosynthesis-related genes, are associated with and influence biopterin levels, and are candidate SZ susceptibility loci. We will employ Re- Sequencing Arrays to screen for DNA variants that may influence gene expression and/or protein function. Sequence data generated in this study will be analyzed for association with low biopterin levels and subject diagnosis. The Specific aims of this proposed study are: Aim 1a. To design Re-Sequencing arrays that include the gene regulatory regions, intron-exon boundaries, and coding regions for the six BH4 biosynthesis pathway genes, plus 13 additional BH4 regulation-associated genes. 1b. To generate gene sequence data for 180 subjects (90 SZ subjects and 90 controls), all with assayed plasma biopterin levels. Aim 2. To analyze the sequence data using single marker association testing and haplotype analyses, and to identify DNA variants associated with SZ and biopterin deficit. Understanding the genetic basis of the SZ biopterin deficit will be primary to development of medications and may also allow pre-symptomatic and early diagnostic testing, and early treatment that may improve the clinical outcomes for persons at risk of developing SZ. 7. PROJECT NARRATIVE This study will test whether people with schizophrenia (SZ), who showed abnormally low levels of a chemical called BH4 that is very important for brain function, also have DNA abnormalities in the genes that produce BH4. If they do, we will look for ways to treat low BH4 levels, and try to improve the symptoms of patients that way. We may also be able to predict risk of SZ in people with the gene defect, and therefore may be able to start treatment as early as possible to improve the outcome for those with the disease and young people at risk of developing SZ.