The Role of SLITRK1 in Tourette and Related Disorders

描述(申请人提供)：多发性抽动障碍(TD)是一种发育性神经精神综合征，以慢性发声和运动痉挛的存在为特征，每100名学龄儿童中就有1人受到影响。尽管有相当多的证据表明这与基因有关，但还没有发现与疾病相关的基因。Sit and Trk样家族1(SLITRK1)最近被发现是参与TD的一个强有力的候选基因，最初是通过定位一个三代家系中唯一受影响的成员的从头染色体异常。随后对204个先证者进行了突变筛选，发现：1)一个截短移码突变存在于两个患病家族成员中，并且在三个未患病家庭成员中缺失，并且在3600条对照染色体中未发现；2)在2个患病同胞中，跨膜区的一个高度保守的氨基酸发生了非同义替换，在4000条对照染色体中不存在；以及3)在两个无关的个体中，脑结合区域高度保守的核苷酸上的相同单碱基置换表达了microRNA-189(miR-189)，而在4296条对照染色体中不存在。表达分析表明，SLITRK1mRNA和miR-189在被认为与TD发病相关的脑区重叠。在发育中的皮质神经元中，野生型Slitrk1的过表达，而不是移码突变体，促进了树突的伸长。我们现在建议通过儿科精神病学、遗传学和神经生物学的持续跨学科合作，进一步研究SLITRK1在TD中的作用。具体地说，我们的目标是：1)在TD及相关疾病的扩大患者组中搜索SLITRK1的其他突变；2)进一步鉴定SLITRK1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；以及4)确定与SLITRK1相互作用的蛋白质，作为这些基因突变筛选的前奏。SLITRK1是一种基因，在一些抽动症(TD)病例中发现少数患者有罕见的DNA序列变化，而这些变化在未受影响的人中没有发现。这项研究的目的是通过识别SLITRK1基因中的其他异常并通过调查这些不寻常的基因变化对发育中的大脑的影响来更好地了解TD的原因。

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.