MOLECULAR GENETIC STUDIES OF SEROTONIN FUNCTION

对5-羟色胺功能有遗传缺陷的个体和动物的研究可以揭示这种神经递质在行为中的作用，以及5-羟色胺基因中较温和的功能变体在使个体易患精神病理学和酗酒中的作用。我们正在通过测量脑脊液中5-羟色胺代谢物5-HIAA和确定与5-羟色胺功能有关的基因中氨基酸取代的个体来确定家族研究的先证者。两个5-HT 1A变体是罕见的氨基酸取代（Gly 22 Ser和Val 28 Ile），一个保守，一个非保守。5-HT 2C变异是一种常见的（等位基因频率=0.18）非保守性取代（Cys 23 Ser）。两个5 HT 2A氨基酸取代（Ala 477 Val和His 452 Tyr）具有0.01和0.09的等位基因频率。还发现了罕见的5-羟色胺转运体和5-HT 7氨基酸取代。这些氨基酸取代中的三个显示出改变相应受体的功能特性。当在CHO-K1细胞中表达时，5 HT 1A Gly 22 Ser显著改变了这些受体的脱敏和下调。卵母细胞和COS-7细胞中的5 HT 2C Cys 23 Ser降低配体结合，5 HT 2A His 452 Tyr损害来自具有452 Tyr等位基因的受试者的血小板中的信号转导。为了关联和直接基因分析，我们从以下人群中收集了40多个细胞系：神经性厌食症（与W。Kaye）、强迫症（D. Murphy），低CSF 5-HIAA与II型酒精中毒（M。林诺伊拉湾Virkkunen，M. Eggert）和季节性情感障碍（N. Rosenthal，N. Ozaki）。将检测到的多态性转化为PCR RFLP或等位基因特异性扩增标记以便于分析。使用CEPH参考家系和这些基因的多态性，每个基因被遗传映射到其染色体位置。对于直接基因分析，我们主要采用单链构象多态性分析和直接测序。TPH多态性与冲动性酗酒芬兰人自杀倾向的关联被复制。在芬兰人（J. Lappalainen）中发现了5 HT 1B与反社会酗酒的同胞对联系，并在美国西南部的印第安人中复制。5-羟色胺转运蛋白启动子变异体5-HTTLPR以前与神经质有关，在同胞对分析中与TPQ的两个焦虑相关分量表有关（C。马赞蒂），部分复制了早期的发现。在一系列出版物中，我们已经表明5 HT 2A-1438 G>A启动子变体与焦虑相关病症相关。这些包括强迫症，季节性情感障碍，神经性厌食症和三维人格问卷中的焦虑相关量表。- 人口研究，神经科学，基因图谱（人类），分子遗传学，饮酒模式和原因

Studies on individuals and animals with genetic defects in serotonin function can shed light on the role of this neurotransmitter in behavior and on the role of milder functional variants in serotonin genes in predisposing individuals to psychopathologies and to alcoholism. We are identifying probands for family studies by measuring the serotonin metabolite 5-HIAA in cerebrospinal fluid and by identifying individuals with amino acid substitutions in genes involved with serotonin function. Two 5-HT1A variants are rare amino acid substitutions (Gly22Ser and Val28Ile), one conservative and one nonconservative. The 5-HT2C variant is a common (allele frequency=0.18) nonconservative substitution (Cys23Ser). Two 5HT2A amino acid substitutions (Ala477Val and His452Tyr) have allele frequencies of 0.01 and 0.09. Rare serotonin transporter and 5-HT7 amino acid substitutions were also discovered. Three of these amino acid substitutions were shown to alter the functional properties of the corresponding receptor. 5HT1A Gly22Ser when expressed in CHO-K1 cells dramatically altered desensitization and down regulation of these receptors. 5HT2C Cys23Ser in oocytes and COS-7 cells decreased ligand binding 5HT2A His452Tyr impaired signal transduction in platelets from subjects with the 452Tyr allele. For association and direct gene analysis, we have collected more than 40 cell lines from each of the following populations: anorexia nervosa (collaboratively with W. Kaye), obsessive compulsive disorder (D. Murphy), low CSF 5-HIAA with Type II alcoholism (M. Linnoila, M. Virkkunen, M. Eggert), and seasonal affective disorder (N. Rosenthal, N. Ozaki). The detected polymorphisms are converted to PCR RFLPs or allele-specific amplification markers for ease of analysis. Using the CEPH reference pedigrees and the polymorphisms at these genes, each gene is genetically mapped to its chromosomal location. For direct gene analysis, we mainly use single-strand conformational polymorphism analysis and direct sequencing. Association of a TPH polymorphism with suicidality in impulsive alcoholic Finns was replicated. Sib-pair linkage of 5HT1B to antisocial alcoholism was found in Finns (J. Lappalainen) and replicated in Southwestern American Indians. The serotonin transporter promoter variant 5-HTTLPR which was previously linked to neuroticism was linked to the two anxiety related subscales of the TPQ in a sib pair analysis (C. Mazzanti), partially replicating an earlier finding. In a series of publications, we have shown that the 5HT2A-1438 G>A promoter variant is linked to anxiety related conditions. These include OCD, seasonal affective disorder, anorexia nervosa and anxiety-related scales from the Tridimensional Personality Questionnaire. - population research, neurosciences, gene mapping (human), molecular genetics, drinking patterns & causes