MOLECULAR GENETIC STUDIES OF SEROTONIN FUNCTION

具有遗传基因的个体和动物研究 5-羟色胺功能的缺陷可以阐明这一作用 神经递质在行为和温和功能中的作用 5-羟色胺基因变异与易感人群的关系 精神变态和酗酒。我们正在辨认先证者 用于家庭研究通过测量5-羟色胺代谢物5-HIAA 脑脊液和通过氨基酸鉴定个体 5-羟色胺功能相关基因的替换。二 5-HT1a变异体是罕见的氨基酸替代(Gly22Ser和 Val28Ile)，一个保守，一个非保守。5-HT2C 变异是一种常见的(等位基因频率=0.18)非保守性 替换(Cys23Ser)。两个5HT2A氨基酸替换 (Ala477Val和His452Tyr)的等位基因频率分别为0.01和 0.09。罕见的5-羟色胺转运体和5-HT7氨基酸 还发现了替代基因。其中三种氨基酸 替换被证明改变了功能属性 相应的受体。5HT1AGly22Ser表达时 CHO-K1细胞显著改变了脱敏和下调 对这些受体的调节。5HT2C Cys23Ser在卵母细胞和 COS-7细胞5HT2AHis452Tyr受损的配体结合减少 452Tyr等位基因受试者的血小板信号转导。 对于关联和直接基因分析，我们收集了更多 来自以下每个群体的40多个细胞系：厌食症 神经质(与W.Kaye合作)，强迫症 精神障碍(D.Murphy)，低脑脊液5-HIAA合并II型酒精中毒 (M.LInnoila，M.Virkkunen，M.Eggert)和季节性情感 障碍(N.Rosenthal，N.Ozaki)。检测到的多态是 转化为PCRRFLP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，每个基因都被遗传定位到 它的染色体位置。对于直接的基因分析，我们主要使用 单链构象多态性分析和直接测序 测序。促甲状腺激素释放激素基因多态性与自杀的关系 冲动的酗酒芬兰人也被复制了。5HT1b的SIB对连锁 在芬兰人中发现了反社会的酒精中毒(J.拉帕莱宁)和 在美国西南部的印第安人身上也是如此。最后，血清素 转运蛋白启动子变异体5-HTTLPR 与神经质有关的两种焦虑有关 同胞配对分析中的TPQ分量表(C.Mazzanti)，部分 复制了早先的发现。

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.