The Role of SLITRK1 in Tourette and Related Disorders

描述（由申请人提供）：图雷特障碍（TD）是一种发育性神经精神综合征，由慢性声音和运动抽搐的存在所定义，影响多达1 / 100的学龄儿童。尽管有相当多的证据表明遗传因素起作用，但尚未发现与疾病相关的基因。SLIT和trk样家族1 （SLITRK1）最近被发现是参与TD的一个强有力的候选者，最初是通过在一个三代谱系中唯一受影响的成员中定位一个新发染色体异常。对204个先证基因进行突变筛选后发现：1)截断移码突变在2个受影响的家庭成员中存在，在3个未受影响的家庭成员中不存在，在3600条对照染色体中未发现；2)在2个受影响的兄弟姐妹中，跨膜结构域高度保守的氨基酸发生非同义替换，而在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）结合区域高度保守的核苷酸上的相同单碱基替换，在4296条对照染色体中不存在。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重叠。在发育中的皮质神经元中，过度表达野生型Slitrkl而非移码突变体促进树突伸长。我们现在建议通过持续的跨学科合作，包括儿科精神病学、遗传学和神经生物学，进一步研究SLITRK1在TD中的作用。具体来说，我们的目标是：1)在扩大的TD和相关疾病患者群体中寻找SLITRK1的其他突变；2)进一步表征SLITRK1 RNA和蛋白在发育小鼠和人脑中的表达；3)阐明野生型和突变型SLITRK1在皮质神经元发育中的作用；4)鉴定与SLITRK1相互作用的蛋白，作为筛选这些基因突变的前奏。SLITRK1是一种与某些图雷特病（TD）有关的基因，在少数未受影响的患者中发现了罕见的DNA序列变化。本研究的目的是为了更好地理解。通过识别SLITRK1基因中的其他异常，并通过研究这些不寻常的遗传变化对发育中的大脑的影响，来研究导致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.