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: 7675963
• 负责人: MATTHEW W. STATE
• 金额: $ 41.6万
• 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/7675963
• 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; Cell Culture Techniques; Child; Childhood; Chromosome abnormality; Chromosomes; Chromosomes, Human, Pair 2; Chromosomes, Human, Pair 3; Chronic; Cleaved cell; Co-Immunoprecipitations; Code; Collaborations; Collection; Complement; 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; Obsessive-Compulsive Disorder; Partner in relationship; Pathogenesis; Patients; Pattern; Persons; Phenotype; Polygenic Traits; Proteins; Psychiatry; RNA; RNA Interference; Regulation; Reporter; Repression; Research Personnel; Resources; Role; School-Age Population; Screening procedure; Siblings; Single base substitution; Syndrome; System; Temperature; Thalamic structure; 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 therapeutic intervention; overexpression; 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）：妥瑞氏症（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性抽搐，影响多达1/100的学龄儿童。尽管有相当多的遗传贡献的证据，没有疾病相关的基因已被确定。SLIT和Trk样家族1（SLITRK 1）最近被发现是参与TD的强有力的候选者，最初是通过在三代系谱中唯一受影响的成员中定位从头染色体异常。对204例先证者进行突变筛查，发现：1）在2例患者中发现一个截短移码突变，在3例未患病的家系成员中发现，在3600条对照染色体中未发现; 2）在2例患者同胞中发现一个跨膜区高度保守的非同义替换，在4000条对照染色体中未发现;以及3）在两个无关个体中，在脑表达的microRNA-189（miR-189）的结合结构域中高度保守的核苷酸处的相同的单碱基取代，而不存在于4296个对照染色体中。表达分析表明，SLITRK 1 mRNA和miR-189在被认为与TD发病机制相关的脑区域重叠。野生型Slitrkl的过表达，但不是移码突变体，在发育中的皮层神经元促进树突状细胞的伸长。我们现在建议通过儿科精神病学、遗传学和神经生物学等持续的跨学科合作，进一步研究SLITRK 1在TD中的作用。具体而言，我们的目标是：1）在扩展的TD和相关疾病患者组中寻找SLITRK 1的其他突变; 2）进一步表征发育中的小鼠和人脑中SLITRK 1 RNA和蛋白质的表达; 3）阐述野生型和突变型SLITRK 1在发育中的皮质神经元中的功能;和4）鉴定与SLITRK 1相互作用的蛋白质，作为这些基因突变筛选的前奏。SLITRK 1是一种与某些抽动秽语障碍（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没有发现这种变化。这项研究的目的是通过确定SLITRK 1基因中的其他异常并通过调查这些不寻常的遗传变化对发育中的大脑的影响来更好地了解TD的原因。