MOLECULAR STUDIES ON GENETIC VARIANTS OF TRYPTOPHAN HYDR

脑脊液(CSF)5-HIAA 5-羟色胺的代谢物，可以识别缺乏5-羟色胺 中枢神经系统5-羟色胺代谢。5-羟色胺减少 新陈代谢，如低脑脊液5-HIAA所表明的，被认为是 与缺乏冲动控制的行为有关 包括酗酒。脑脊液5-HIAA的性状差异 浓度集中可能是由于调节基因的遗传变异造成的 5-羟色胺代谢。找出控制因素 5-羟色胺依赖的行为，我们将努力集中在 色氨酸羟基酶(TPH)是人体内的限速酶。 5-羟色胺和5-羟色胺受体的生物合成， 调节5-羟色胺能活动。TPH中的第一个变种是 人TPH基因的鉴定及其在染色体上的定位 11p15.5位于TPH内含子7的变异体被发现是 与脑脊液中5-HIAA浓度有关的酗酒，冲动， 芬兰罪犯。与自杀史相关的变异 酒鬼芬兰语中的自杀未遂和多次自杀未遂 违法者。这一发现与TPH变异与 自杀行为在一群新的芬兰人中复制 酗酒者。TPH连锁的证据被发现 酗酒、自杀、KSP社交得分。在其他 研究表明，TPH基因与儿童自杀之间的关系 抑郁症患者与冲动性攻击行为的关系 发现有人格障碍患者。对TPH基因进行了测序 来自两个等位基因纯合的个体，并且没有改变 观察到了mRNA的剪接。几乎整个编码区 已经对TPH基因进行了分析，只有一个罕见的沉默变体 被发现了。对上游序列的分析已经确定了三个 其他变种。这些基因已经被融合到一个记者基因上 正在进行分析。EMSA分析显示差异结合 影响变异等位基因的因素。人类5-HT1a的三个变种 基因已被单链构象鉴定 多态(SSCP)分析。两个变种会改变蛋白质 序列，第三个是沉默的。序列中的Ser22变种 人5-HT1a受体胞外氨基末端 减少激动剂促进的下调和脱敏 受体表达。此外，一种等位基因变异已经被 在红毛猴的5-HT1a基因中被鉴定。

Cerebral spinal fluid (CSF) 5-HIAA, the principal metabolite of serotonin, can identify individuals with a deficit of central nervous system serotonin metabolism. Decreased serotonin metabolism, as indicated by low CSF 5-HIAA, is postulated to be connected with behaviors characterized by deficient impulse control including alcoholism. Trait differences in CSF 5-HIAA concentration may be due to genetic variants of genes regulating serotonin metabolism. To identify factors controlling serotonin-dependent behaviors, we have focused our efforts on tryptophan hydroxylase (TPH), the rate-limiting enzyme in the biosynthesis of serotonin, and the 5-HT receptor which, in part, regulates serotonergic activity. A variant, the first in TPH, was identified and used to map the human TPH gene to chromosome 11p15.5 The variant, which is in intron 7 of TPH, was found to be associated with CSF 5-HIAA concentration in alcoholic, impulsive, Finnish offenders. The variant associated with a history of suicidal attempts and of multiple suicidal attempts in alcoholic Finnish offenders. This finding of an association of the TPH variant with suicidal behavior has been replicated in a new population of Finnish alcoholic offenders. Evidence for linkage of TPH was found to alcoholism, suicidality, and KSP socialization score. In other studies, an association of TPH genotype with suicidality in depressed patients and to impulsive-aggressive behavior in personality disorder patients was found. TPH cDNA was sequenced from individuals homozygous for both alleles and no alteration in mRNA splicing was observed. Nearly the entire coding region of the TPH gene has been analyzed and only one rare silent variant was found. Analysis of the upstream sequences have identified three additional variants. These have been fused to a reporter gene and are being analyzed. EMSA analysis revealed differential binding of factors to the variant alleles. Three variants of the human 5-HT1A gene have been identified by single-strand conformational polymorphism (SSCP) analysis. Two variants change the protein sequence and the third is silent. The Ser22 variant in the extracellular amino-terminus of the human 5-HT1A receptor decreases agonist-promoted down-regulation and desensitization of receptor expression. In addition, an allelic variant has been identified in the 5-HT1A gene in vervet monkeys.