Genetics of Adult Idiopathic Hydrocephalus

特发性正常压力性脑积水(INPH)是一种以衰老为特征的神经功能紊乱。 脑室扩大、步态困难、大小便失禁和痴呆症。这是一种常见的疾病 几乎只发生在60岁以后。约1.3%的65岁以上患者和9%-14%的 疗养院的居民被认为患有INPH。不幸的是，90%以上的患者 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者不熟悉 患上了这种疾病。INPH的病因尚不清楚。零星的家族性INPH病例报告表明 这是一种基因起源，但涉及的基因尚不清楚。为了研究这一问题，我们使用了exome 测序以寻找与INPH相关的遗传因素。我们发现反复出现的杂合子突变 10个基因，几乎所有基因都在纤毛上皮和/或 脉络丛。许多以前被认为与纤毛的功能有关。SiRNA介导的 其中几个基因的敲除在体内增加了脑室大小，其中一个基因的敲除 在体内也显示出减少纤毛数量和长度的作用。重要的是，我们和其他人发现 在人类和小鼠中，心室体积随着年龄的增长而增加，我们观察到纤毛数量和 小鼠的身长随着年龄的增长而减少。这项提议将使用完整的外显子组测序和体外和 用活体小鼠模型来检验这一假说，即损害细胞功能的杂合性突变 活动的纤毛，加上与年龄相关的纤毛室管膜细胞功能的下降，导致INPH。如果 如果成功，这些发现可能会提高对INPH的理解、诊断或治疗。

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.