Genetics of Adult Idiopathic Hydrocephalus

特发性正常压力脑积水（iNPH）是一种老年神经系统疾病，其特征是 脑室扩大、步态困难、大小便失禁和痴呆。这是一种常见的疾病， 几乎都发生在60岁以后。约1.3%的65岁以上患者和9-14%的 养老院的居民被认为患有iNPH。不幸的是，超过90%的患者 仍然被误诊或未诊断，部分原因是iNPH的症状类似于 其他神经退行性疾病，部分原因是许多卫生保健从业人员不熟悉 这种紊乱。iNPH的病因尚不清楚。iNPH家族性病例的零星报告表明 基因起源，但涉及的基因未知。为了研究这个问题，我们使用了外显子组 测序以寻找与iNPH相关的遗传因素。我们发现了复发性杂合突变， 10个基因，几乎所有这些基因在纤毛心室上皮中表达增加，和/或 脉络丛许多以前与纤毛的功能有关。sirna介 敲除这些基因中的几个增加了体内心室的大小，敲除这些基因中的一个增加了体内心室的大小。 也显示出减少纤毛的数量和长度在体内。重要的是，我们和其他人发现， 在人类和小鼠中，心室容积随着年龄的增长而增加，我们观察到纤毛数量和 在小鼠中长度随着年龄的增长而减少。该建议将使用全外显子组测序，并在体外和体内进行 体内小鼠模型，以测试杂合突变，损害功能的假设， 运动纤毛与年龄相关的纤毛室管膜细胞功能下降相结合，导致iNPH。如果 如果成功，这些发现可能会导致对iNPH的理解，诊断或治疗的改善。

Idiopathic normal pressure hydrocephalus (iNPH) is a neurological disorder of aging that is characterized by enlarged cerebral ventricles, gait difficulty, incontinence and dementia. It is a common disorder that occurs almost exclusively after the age of 60. About 1.3% of patients over the age of 65 and 9-14% of nursing home residents are thought to have iNPH. Unfortunately, more than 90% of these patients remain misdiagnosed or undiagnosed, in part because the symptoms of iNPH resemble the symptoms of other neurodegenerative diseases, and in part because many health care practitioners are unfamiliar with this disorder. The etiology of iNPH is not known. Scattered reports of familial cases of iNPH suggest a genetic origin, but the genes involved are unknown. To investigate this matter, we have used exome sequencing to look for genetic factors associated with iNPH. We find recurrent heterozygous mutations in 10 genes, nearly all of which show increased expression in the ciliated ventricular epithelium and/or choroid plexus. Many have previously been associated with the function of cilia. siRNA-mediated knockdown of several of these genes increased ventricular size in vivo, and knockdown of one of these was also shown to decrease cilia number and length in vivo. Importantly, we and others find that ventricular volume increases with age in humans and in mice, and we observed that cilia number and length decreases with age in mice. This proposal will use whole exome sequencing and in vitro and in vivo mouse models to test the hypothesis that heterozygous mutations that compromise the function of motile cilia, combined with age-related declines in ciliated ependymal cell function, lead to iNPH. If successful, the findings may lead to improved understanding, diagnosis or treatment of iNPH.