TRYPTOPHAN 2,3-DIOXYGENASE--CANDIDATE GENE FOR SEROTONIN METABOLISM DISORDERS

色氨酸 2,3-双加氧酶——血清素代谢紊乱的候选基因

• 批准号: 6431387
• 负责人: MARY ANNE ENOCH
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6431387
• 关键词: SDS polyacrylamide gel electrophoresis; alcoholism /alcohol abuse; anorexia nervosa; autism; behavioral genetics; bulimia nervosa; enzyme deficiency; genetic polymorphism; genetic promoter element; human genetic material tag; impulsive behavior; inborn metabolism disorder diagnosis; linkage mapping; major depression; neurotransmitter metabolism; nucleic acid repetitive sequence; obsessive compulsive disorder; serotonin; single strand conformation polymorphism; suicide; transposon /insertion element; tryptophan 2,3 dioxygenase

Genetic defects in the enzymes involved in serotonin metabolism may contribute to a wide range of neuropsychiatric diseases, from eating disorders, obsessive-compulsive disorder andalcoholism to autism. Tryptophan, obtained only from the diet in humans, is converted to serotonin by tryptophan hydroxylase, or to kynurenine by tryptophan 2,3-dioxygenase (TDO2). Both enzymes are rate limiting in their respective pathways. The purpose of this study is to screen the TD02 gene forpolymorphisms, assess functionality, and search for disease associations in 350 individuals, primarily using single-strand conformational polymorphism (SSCP) analysis. Most of the coding region (11 of the 12 exons) and short regions of the introns was successfully amplified and screened across populations with anorexia or bulimia nervosa, obsessive-compulsive disorder, autism, major depression and suicidality, impulsivity and alcoholism, and subjects enrolled in a tryptophan depletion study. No associations were found for polymorphisms in introns 5, 6 and 11 nor for a variant in exon 7 (A to C, 749 Asn to His). In the SSCP screening of the promoter region no polymorphisms were found in the regions of two TATA boxes. An A to C variant was detected in the putative glucocorticoid site but was not associated with disease. However, in the promoter region of GTT repeats, a GTT insertion was found which may be associated with impulsivity and novelty seeking but not with alcoholism. Three further polymorphisms have now been found in the promoter region and are in the process of being sequenced and screened across populations.

5-羟色胺代谢涉及的酶中的遗传缺陷可能导致多种神经精神疾病，从饮食失调，强迫症和自闭症患者到自闭症。色氨酸仅从人类饮食中获得的色氨酸通过色氨酸羟化酶或色氨酸2,3-二氧酶（TDO2）转化为5-羟色胺。 这两种酶在其各自途径中都是限制的。 这项研究的目的是筛选TD02基因效应，评估功能性和在350名个体中寻找疾病关联，主要是使用单链构象多态性（SSCP）分析。 大多数编码区域（12个外显子中的11个）和内含子的短区域都成功地放大并筛选了厌食症或神经性贪食症，强迫症，自闭症，重度抑郁症和自杀，冲动性和酗酒的人群，以及参与apptpophan Deppopophan Deptletion研究的受试者。 在内含子5、6和11中，未发现任何相关性，也没有在外显子7（A至C，749 ASN）中的变体中发现。在启动子区域的SSCP筛选中，在两个塔塔盒的区域中未发现多态性。在假定的糖皮质激素部位检测到A至C变体，但与疾病无关。但是，在GTT重复的启动子区域中，发现GTT插入可能与冲动性和新颖性有关，但与酒精中毒无关。现在在启动子区域中发现了另外三种多态性，并且正在对种群进行测序和筛查。