MOLECULAR GENETIC STUDIES OF SEROTONIN FUNCTION

对具有遗传病的个体和动物的研究 5-羟色胺功能的缺陷可以揭示这一作用， 神经递质在行为和轻度功能性 在易患糖尿病的个体中， 精神病和酗酒我们正在确定先证者 通过测量5-羟色胺代谢物5-HIAA的家庭研究， 脑脊液和通过识别具有氨基酸的个体 5-羟色胺功能相关基因的替换。两 5-HT 1A变体是罕见的氨基酸取代（Gly 22 Ser和Gly 22 Ser）。 Val 28 Ile），一个保守的和一个非保守的。5-HT2C 变异是一个常见的（等位基因频率=0.18）非保守 取代（Cys 23 Ser）。两个5 HT 2A氨基酸取代 （Ala 477 Val和His 452 Tyr）的等位基因频率为0.01， 0.09.罕见的5-羟色胺转运体和5-HT 7氨基酸 还发现了一些替代品。其中三种氨基酸 取代显示出改变了 相应的受体。5 HT 1A Gly 22 Ser在大肠杆菌中表达时， CHO-K1细胞显著改变了脱敏， 调节这些受体。卵母细胞中的5 HT 2C Cys 23 Ser， COS-7细胞减少的配体结合5 HT 2A His 452 Tyr受损 来自具有452 Tyr等位基因的受试者的血小板中的信号转导。 对于关联和直接基因分析，我们收集了更多 来自以下群体中的每一个的40个以上细胞系： nervosa（与W. Kaye）、强迫症 disorder（D. Murphy），低CSF 5-HIAA伴II型酒精中毒 （M.林诺伊拉湾Virkkunen，M. Eggert），以及季节性情感 disorder（N. Rosenthal，N. Ozaki）。检测到的多态性是 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 在这些基因的多态性，每个基因是遗传映射到 它的染色体位置。对于直接基因分析，我们主要使用 单链构象多态性分析和定向 测序TPH基因多态性与儿童自杀倾向的相关性研究 冲动的酗酒芬兰人被复制。5 HT 1B的同胞对连接 在芬兰人中发现了反社会酒精中毒（J. Lappalainen）， 在美国西南部的印第安人身上复制。最后，血清素 转运蛋白启动子变体5-HTTLPR，其先前是 与神经质有关的两种焦虑 同胞对分析中TPQ的分量表（C。Mazzanti），部分 复制了之前的发现

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. Finally, 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.