Biopterin Deficit in Schizophrenia: Genetic Dissection of BH4 Biosynthesis.

精神分裂症中的生物蝶呤缺乏症：BH4 生物合成的基因剖析。

• 批准号: 7364204
• 负责人: JAMES Donald CLELLAND
• 金额: $ 16.2万
• 依托单位: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-19 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7364204
• 关键词: Alleles; Amines; Anabolism; Biological Assay; Biopterin; Brain; Chemicals; Clinical; Code; DNA; Data; Defect; Development; Diagnosis; Diagnostic tests; Disease; Dissection; Dopamine; Early treatment; Employee Strikes; Etiology; Excretory function; Exons; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic screening method; Genotype; Glutamates; Haplotypes; Human; Introns; Maintenance; Measures; Mus; Neurotransmitters; Nitric Oxide; Nucleic Acid Regulatory Sequences; Numbers; Odds Ratio; Outcome; Pathogenesis; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Physiological; Plasma; Predisposition; Prevalence; Regulation; Reporting; Risk; Role; Sampling; Schizophrenia; Sequence Analysis; Serotonin; Source; Symptoms; System; Testing; United States National Institutes of Health; Variant; abstracting; base; cofactor; design; improved; protein function; tetrahydrobiopterin; urinary

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.

描述（由申请人提供）：四氢生物蝶呤（BH 4）是一种重要的辅因子，可维持包括多巴胺和5-羟色胺在内的胺神经递质的可用性，调节一氧化氮合成，并刺激和调节谷氨酸能系统。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BH 4在NT合成中的核心作用，我们在SZ患者和对照组的大样本中测定了血浆总生物蝶呤水平（BH 4的测量）。与对照组相比，SZ患者组观察到34%的高度显著的平均生物蝶呤缺乏。观察到的生物蝶呤赤字是可比的遗传BH 4缺乏症的报告，支持其表征具有生理意义。我们高度重要的发现，沿着：a）已知的BH 4在NT维持中的作用，B）在人类和小鼠BH 4缺乏中观察到的CNS NT合成的失调，c）血浆生物蝶呤水平与CNS生物蝶呤水平相关的证据，和d）SZ中尿生物蝶呤排泄没有增加的证据，都支持我们的假设，即BH 4生物合成的失调与SZ的病因学有关。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BH 4生物合成途径中的第一个基因GCH 1进行了初步基因检测，对132例受试者（86例SZ和46例对照受试者）的样本中与SZ相关的多态性进行了基因分型。结果是惊人的：我们发现GCH 1与SZ密切相关：比值比，5.0，p= 0.0057。我们还发现，GCH 1等位基因状态预测SZ患者的低生物喋呤。基于这些非常积极的初步数据，以及一些没有SZ相关GCH 1基因型的SZ受试者也有生物蝶呤缺陷的事实，本探索性研究旨在检验GCH 1和其他BH 4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，并且是候选SZ易感基因座的假设。我们将使用重新测序阵列来筛选可能影响基因表达和/或蛋白质功能的DNA变体。将分析本研究中生成的序列数据与低生物蝶呤水平和受试者诊断的相关性。本研究的具体目标是：目标1a。设计包括基因调控区、内含子-外显子边界和6个BH 4生物合成途径基因的编码区以及13个额外的BH 4调控相关基因的重测序阵列。1b.生成180名受试者（90名SZ受试者和90名对照）的基因序列数据，所有受试者均测定了血浆生物蝶呤水平。目标二。利用单标记关联检验和单倍型分析对序列数据进行分析，并鉴定与SZ和生物蝶呤缺陷相关的DNA变异。了解SZ生物蝶呤缺乏的遗传基础将是主要的药物开发，也可能允许症状前和早期诊断测试，早期治疗，可能会改善临床结果的人在发展SZ的风险。7.这项研究将测试精神分裂症（SZ）患者是否也存在产生BH 4的基因中的DNA异常，这些患者显示出异常低水平的一种名为BH 4的化学物质，这种化学物质对大脑功能非常重要。如果他们这样做，我们将寻找治疗低BH 4水平的方法，并试图改善患者的症状。我们也可能能够预测SZ的风险与基因缺陷的人，因此可能能够尽早开始治疗，以改善那些与疾病和年轻人在发展SZ的风险的结果。

项目成果

Evidence that COMT genotype and proline interact on negative-symptom outcomes in schizophrenia and bipolar disorder.

• DOI: 10.1038/tp.2016.157
• 发表时间: 2016-09-13
• 期刊: Translational psychiatry
• 影响因子: 6.8
• 作者: Clelland CL;Drouet V;Rilett KC;Smeed JA;Nadrich RH;Rajparia A;Read LL;Clelland JD
• 通讯作者: Clelland JD