Molecular Cytogenetics and Tourette Disorder

分子细胞遗传学和抽动秽语症

• 批准号: 6624303
• 负责人: MATTHEW W. STATE
• 金额: $ 36.01万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6624303
• 关键词: DNA replication; Tourette's syndrome; artificial chromosomes; behavioral /social science research tag; behavioral genetics; child (0-11); chromosome disorders; chromosome inversion; clinical research; cytogenetics; family genetics; fluorescent in situ hybridization; gene expression; gene mutation; gene rearrangement; genetic mapping; genetic polymorphism; genetic regulation; high performance liquid chromatography; human genetic material tag; human subject; information dissemination; methylation; neuropsychology; northern blottings; obsessive compulsive disorder; polymerase chain reaction; solution hybridization

The goal of this proposal is to use molecular cytogenetic and molecular genetic tools to identify genes involved in Tourette syndrome (TS) and related phenotypes. TS is a neuropsychiatric disorder defined by the combination of persistent vocal and motor tics. Despite strong evidence for a genetic etiology, linkage studies undertaken over several decades have not yet identified a single gene clearly implicated in TS- spectrum disorders, which include chronic tics (CT) and tic- related Obsessive Compulsive Disorder (OCD). We have undertaken an alternative strategy for disease-gene identification based on the hypothesis that a small subset of patients presenting with this genetically heterogeneous disorder have their symptoms as the result of a structural or functional disruption of a gene of major effect due to a cytogenetic abnormality. We further propose that the identification of such a gene may illuminate biological pathways involved in more common forms of TS. Our lab has identified two patients with TS-related phenotypes: (1) a patient with CT and OCD and an inversion inv(18)(q21q22); and, (2) a patient with OCD and a balanced translocation t(18;2)(q22;p25). These abnormalities map approximately 500 kilobases (kb) and 4 megabases (Mb) respectively from a chromosome 18q22 breakpoint that segregates with TS, CT and OCD in a previously-described family (Bhogosian-Sell et al. 1996). We have obtained cell lines from this pedigree as well and have initiated an exhaustive molecular characterization of the 4.5 Mb interval defined by the three 18q22 breakpoints. Our preliminary data also demonstrates that the 18q22 inversion is altering the replication timing at this locus. This change in the epigenetic properties of the patient's inverted chromosome 18 suggests that the rearrangement is influencing the regulation of gene expression across this region. The data has prompted two associated avenues of investigation: (1) an assessment of the extent of epigenetic changes in all three 18q22 rearrangements; and, (2) an evaluation of the epigenetic properties of the 18q22 region in cytogenetically-normal subjects with TS-spectrum phenotypes. We now propose: (1) to complete the fine-mapping of the three chromosome 18q22 breakpoints at the nucleotide level; (2) to identify known and novel transcripts within the interval defined by these abnormalities; (3) to prioritize genes based on functional and structural data and to conduct mutation screening on selected candidates; (4) to investigate epigenetic phenomena in the region in cytogenetically-affected cases as well as in cytogenetically-normal TS, OCD and CT patients; and, (5) to perform screening karyotypes on well-characterized TS spectrum patients from the Yale Child Study Center and Genetics Clinic as the basis for future mapping experiments.

该提案的目的是使用分子细胞遗传学和分子遗传工具来识别涉及图雷特综合征（TS）和相关表型的基因。 TS是一种神经精神疾病，由持续的声音和运动的结合定义。 尽管有充分的证据表明遗传病因，但几十年来进行的连锁研究尚未确定与TS-光谱疾病有关的单一基因，其中包括慢性抽动（CT）和相关的相关强迫症（OCD）。 我们基于以下假设，采取了一种替代疾病 - 基因鉴定的策略，即伴有这种遗传异质性疾病的一小部分患者由于细胞遗传学异常而导致重大影响基因的结构性或功能中断而具有症状。 我们进一步提出，这种基因的鉴定可能会照亮涉及更常见的TS形式的生物学途径。我们的实验室已经确定了两名患有TS相关表型的患者：（1）CT和OCD患者和反转INV患者（18）（Q21Q22）； （2）患有强迫症和平衡易位的患者T（18; 2）（Q22; p25）。 这些异常绘制了大约500千个酶（Kb）和4兆瓦（MB），分别是从18Q22染色体中的断裂点中分离出来的，这些断裂点在以前描述的家族中用TS，CT和OCD隔离（Bhogosian-Sell等，1996）。我们也从该血统中获得了细胞系，并启动了由三个18q22断点定义的4.5 MB间隔的详尽分子表征。我们的初步数据还表明，18Q22倒置正在改变此基因座的复制时间。 患者倒置染色体18的表观遗传特性的这种变化表明，重排正在影响该区域的基因表达的调节。 数据促使了两个相关的研究途径：（1）评估所有三个18q22重排的表观遗传变化程度； （2）对具有TS谱表型的细胞遗传正常受试者中18q22区域的表观遗传特性的评估。我们现在建议：（1）完成核苷酸水平的三个染色体18q22断点的精细图； （2）在这些异常定义的间隔内识别已知和新颖的转录本； （3）根据功能和结构数据确定基因的优先级，并对选定的候选者进行突变筛查； （4）研究该区域的表观遗传现象以及细胞遗传影响的病例以及细胞遗传正常的TS，OCD和CT患者中的表观遗传学； （5）对耶鲁儿童研究中心和遗传学诊所的特征良好的TS谱系患者进行筛查核型，作为未来映射实验的基础。