The Role of SLITRK1 in Tourette and Related Disorders

SLITRK1 在抽动秽语及相关疾病中的作用

• 批准号: 7494011
• 负责人: MATTHEW W. STATE
• 金额: $ 40.73万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7494011
• 关键词: 3' Untranslated Regions; Affect; Alleles; Amino Acids; Attention deficit hyperactivity disorder; Balanced Chromosomal Translocation; Basal Ganglia; Binding; Biological Assay; Brain; Brain region; Capillary Electrophoresis; Child; Childhood; Chromosome abnormality; Chromosomes; Chromosomes, Human, Pair 2; Chromosomes, Human, Pair 3; Chronic; Cleaved cell; Co-Immunoprecipitations; Code; Collaborations; Collection; Complement; Cultured Cells; DNA Sequence; Data; Dendrites; Development; Disease; Dyes; Face; Family; Family member; Frameshift Mutation; Funding; Generations; Genes; Genetic; Gilles de la Tourette syndrome; Growth; Heterogeneity; Human; Immunohistochemistry; In Situ Hybridization; Individual; Interdisciplinary Study; Investigation; Knockout Mice; Laboratories; Luciferases; Maps; Mediating; Messenger RNA; MicroRNAs; Molecular; Motor Tics; Mus; Mutate; Mutation; Neurobiology; Neurons; Nucleic Acid Regulatory Sequences; Nucleotides; Numbers; Obsessive-Compulsive Disorder; Partner in relationship; Pathogenesis; Patients; Pattern; Persons; Phenotype; Polygenic Traits; Protein Overexpression; Proteins; Psychiatry; Purpose; RNA; RNA Interference; Regulation; Reporter; Repression; Research Personnel; Resources; Role; School-Age Population; Screening procedure; Siblings; Single base substitution; Syndrome; System; Temperature; Thalamic structure; Thinking; Transcript; Translating; Transmembrane Domain; Untranslated Regions; Variant; Work; Yeasts; base; disorder risk; fetal; gene discovery; genetic pedigree; hippocampal pyramidal neuron; human tissue; in vivo; insight; loss of function; member; mutant; neuropsychiatry; neurosurgery; novel therapeutics; proband; programs; protein expression; segregation; yeast two hybrid system

DESCRIPTION (provided by applicant): Tourette Disorder (TD) is a developmental neuropsychiatric syndrome defined by the presence of chronic vocal and motor tics that affects as many as 1 in 100 school aged children. Despite considerable evidence for a genetic contribution, no disease-related genes have been identified. SLIT and Trk-like family 1 (SLITRK1) has recently been found to be a strong candidate for involvement in TD, initially through the mapping of a de novo chromosomal abnormality in the only affected member of a three-generation pedigree. Mutation screening of 204 probands subsequently identified: 1) a truncating frameshift mutation that was present in two affected, and absent in three unaffected family members, and could not be found in 3600 control chromosomes; 2) A non-synonymous substitution at a highly conserved amino acid in the transmembrane domain in 2 affected siblings, not present in 4000 control chromosomes; and 3) in two unrelated individuals, the identical single base substitution at a highly conserved nucleotide in the binding domain for the brain expressed microRNA-189 (miR-189), not present in 4296 control chromosomes. Expression analysis demonstrates that SLITRK1 mRNA and miR-189 overlap in brain regions thought relevant to the pathogenesis of TD. Overexpression of wild-type Slitrkl, but not the frameshift mutant, in developing cortical neurons promotes dendritic elongation. We now propose to investigate further the role of SLITRK1 in TD through a continued cross-disciplinary collaboration involving pediatric psychiatry, genetics and neurobiology. Specifically we aim to: 1) search for additional mutations in SLITRK1 in an expanded group of patients with TD and related disorders; 2) further characterize the expression of SLITRK1 RNA and protein in developing mouse and human brain; 3) elaborate the function of wildtype and mutant SLITRK1 in developing cortical neurons; and 4) identify proteins that interact with SLITRK1 as a prelude to mutation screening of these genes. SLITRK1 is a gene implicated in some cases of Tourette Disorder (TD) by the finding of rare DNA sequence changes in a small number of patients that have not been found in unaffected persons. The purpose of this study is to better understand .what causes TD by identifying additional abnormalities in the SLITRK1 gene and by investigating the impact of these unusual genetic changes on the developing brain.

描述（由申请人提供）：抽动秽语障碍 (TD) 是一种发育性神经精神综合征，定义为存在慢性发声和运动抽搐，影响多达百分之一的学龄儿童。尽管有大量证据表明有遗传因素，但尚未发现与疾病相关的基因。最近发现 SLIT 和 Trk 样家族 1 (SLITRK1) 是参与 TD 的有力候选者，最初是通过对三代谱系中唯一受影响成员的从头染色体异常进行定位。随后对 204 名先证者进行突变筛查，发现：1）截短移码突变存在于两名受影响的家庭成员中，而在三名未受影响的家庭成员中不存在，并且在 3600 条对照染色体中未发现； 2) 2 个受影响的兄弟姐妹的跨膜结构域中高度保守的氨基酸发生非同义取代，但在 4000 条对照染色体中不存在； 3) 在两个不相关的个​​体中，大脑表达的 microRNA-189 (miR-189) 结合域中高度保守的核苷酸发生相同的单碱基替换，而 4296 对照染色体中不存在这种情况。表达分析表明 SLITRK1 mRNA 和 miR-189 在被认为与 TD 发病机制相关的大脑区域中重叠。在发育中的皮层神经元中，野生型 Slitrk1 的过度表达（而非移码突变体）会促进树突伸长。我们现在建议通过涉及儿科精神病学、遗传学和神经生物学的持续跨学科合作，进一步研究 SLITRK1 在 TD 中的作用。具体来说，我们的目标是：1）在更多的 TD 和相关疾病患者中寻找 SLITRK1 的其他突变； 2) 进一步表征SLITRK1 RNA和蛋白在发育中的小鼠和人脑中的表达； 3）阐述野生型和突变型SLITRK1在皮质神经元发育中的功能； 4) 鉴定与 SLITRK1 相互作用的蛋白质，作为这些基因突变筛选的前奏。 SLITRK1 是一种与某些妥瑞氏症 (TD) 病例有关的基因，在少数患者中发现了罕见的 DNA 序列变化，而在未受影响的人中尚未发现这种变化。本研究的目的是通过识别 SLITRK1 基因中的其他异常并研究这些不寻常的基因变化对发育中的大脑的影响，更好地了解导致 TD 的原因。