克莱恩-莱文综合征的遗传基因与相关功能研究

Kleine-Levin syndrome (KLS) is a rare disorder with a prevelance around 1/million persons. It is characterized by recurrent episodes of periodic hypersomnia and, to various degrees, cognitive and mood disturbances, impulsive hyperphagia and behavioral changes often accompanied by hypersexuality and autonomic dysfunction. Although most cases of KLS are sporadic, there may be a genetic predisposition, since familial cases have been described. To detect gene mutation in KLS patients, we will use the next generation sequencing (NGS) technology to search for rare disease variants by sequencing the entire protein-coding sequence, known as the exome, or even the entire human genome. During the past decades, we have collected one family with three KLS case, around 60 sporadic cases and 23 trios with KLS patients and their unaffected parents. All of them had clearcut phenotypes with clinical and PSG data.To approch the goal, we will (1) To search for gene mutations in the familial cases through the exome, and the entire human genome sequencing; (2) To replicate the findings in aim (1) in larger sample of KLS patients;(3) To test the trio to define denovo mutation or inherited gene(s) change;(4) finally, we will study the function of the new genes through animal models with centain gene(s) knockout. The study will identify rare disease variants with NGS, and will shed light on the mechanisms of KLS , and the genetic regulation of sleep-wake cycle in normals, and in patients with circadian rythm sleep disorders.

克莱恩-莱文综合征（Kleine-Levin Syndrome, KLS) 以反复周期性发作的嗜睡、贪吃、性欲异常和情绪障碍为特点，患病率百万分之一，属罕见病。发病有家族聚集性，受遗传基因调控。我们将应用发现罕见病少见高效基因研究策略中的二代测序技术寻找KLS的致病基因并开展功能研究。在前期已经收集了1个多病例家系、60余散发病例和23个核心家系，具有完善的临床和电生理表型(Sleep,2016)，我们将(1)应用全外显子测序、全基因组测序分析，筛选候选基因；(2)在其它患者中进行Sanger验证，确定KLS致病基因; (3)对相关患者的核心家系测序证实致病基因是遗传所致还是突变引起；(4) 通过表型与基因关联分析和应用CRISPR/Cas9 系统，构建相关基因在果蝇和小鼠中同源基因的敲除模型明确基因功能。这一研究对明确KLS的病因和睡眠-觉醒周期转换及生物节律异常的基因调控有重要意义。

克莱恩-莱文综合征（Kleine-Levin Syndrome, KLS) 以反复周期性发作的嗜睡、贪吃、性欲异常和情绪障碍为特点，患病率百万分之一，属罕见病。发病有家族聚集性，受遗传基因调控。本研究在完善了80例患者临床资料、DNA和淋巴细胞样本的同时，发现了3个多患者家系，其中一个家系为单卵双生女均患病。发现了中国周期性嗜睡患者的独特表型，并发现周期性嗜睡在发作期脑脊液下丘脑分泌素水平显著降低，提示周期性嗜睡患者与下丘脑分泌素异常相关。通过够相关基因在果蝇和小鼠中同源基因的敲除模型进行了基因功能的研究。通过测定CSF和血浆L-PGDS对比发现周期性嗜睡患者的血脑屏障功能可能存在问题。课题期间培养博士后2名，毕业博士研究生2名，硕士2名。参加国际学术会议并进行专题或主旨发言6次。举办国际学术会议2次。

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