From the Departments of Neuropsychiatry (Y.M., N.Y., H.O.) and Otolaryngology-Head and Neck Surgery (C.S.), Unit of Translation Medicine, and Department of Human Genetics (S.Y., A.K., H.M., K.-i.Y., S.O.), Nagasaki University Graduate School of Biomedical Sciences; Department of Tumor and Diagnostic Pathology, Atomic Bomb Disease Institute (K.M., M.N.), Central Laboratory, Institute of Tropical Medicine (NEKKEN) (M.S.), and Gene Research Center, Center for Frontier Life Sciences (T.K.), Nagasaki University; Department of Infectious Diseases (T.T.) and Child and Adolescent Psychiatry Community Partnership Unit (A.I.), Nagasaki University Hospital; Department of Cell Pathology (Y.K.), Graduate School of Medical Sciences, Kumamoto University; and Department of Clinical Psychology, Faculty of Medicine (N.K.), Kagawa University, Takamatsu, Japan.
Neurology. 2019 May 14;92(20):e2364-e2374. doi: 10.1212/WNL.0000000000007505. Epub 2019 Apr 19.
To identify genes related to normal-pressure hydrocephalus (NPH) in one Japanese family with several members with NPH.
We performed whole-exome sequencing (WES) on a Japanese family with multiple individuals with NPH and identified a candidate gene. Then we generated knockout mouse using CRISPR/Cas9 to confirm the effect of the candidate gene on the pathogenesis of hydrocephalus.
In WES, we identified a loss-of-function variant in that segregated with the disease. encoding cilia- and flagella-associated protein is preferentially expressed in the testis. Recent studies have revealed that mutations in this gene cause male infertility owing to morphologic abnormalities of sperm flagella. We knocked out mouse ortholog using CRISPR/Cas9 technology, resulting in -deficient mice that exhibited a hydrocephalus phenotype with morphologic abnormality of motile cilia.
Our results strongly suggest that is responsible for morphologic or movement abnormalities of cilia in the brain that result in NPH.
在一个有多名正常压力脑积水（NPH）患者的日本家族中，鉴定与 NPH 相关的基因。
我们对一个有多名 NPH 患者的日本家族进行了全外显子组测序（WES），并鉴定了一个候选基因。然后，我们使用 CRISPR/Cas9 生成了敲除小鼠，以确认候选基因对脑积水发病机制的影响。
在 WES 中，我们发现了一个在该家族中与疾病共分离的功能丧失变异。编码纤毛和鞭毛相关蛋白的 优先在睾丸中表达。最近的研究表明，该基因的突变导致精子鞭毛形态异常，引起男性不育。我们使用 CRISPR/Cas9 技术敲除了小鼠同源物 ，导致 缺失小鼠表现出脑积水表型，并伴有运动纤毛形态异常。
我们的结果强烈提示 是导致脑内纤毛形态或运动异常从而引发 NPH 的原因。
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