Nonsense mutation in CFAP43 causes normal-pressure hydrocephalus with ciliary abnormalities
Nonsense mutation in CFAP43 causes normal-pressure hydrocephalus with ciliary abnormalities
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DOI：
10.1212/wnl.0000000000007505
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发表时间：
2019-05-14
期刊：
影响因子：
9.9
通讯作者：
Ono, Shinji
中科院分区：
文献类型：
--
作者：
Morimoto, Yoshiro;Yoshida, Shintaro;Ono, Shinji
目的利用正常压力性脑积水(NPH)日本家系成员进行全外显子测序(WES)，确定与NPH相关的基因。然后我们利用CRISPR/Cas9建立了基因敲除小鼠，以证实候选基因在脑积水发病机制中的作用。结果在WES中，我们发现了与疾病分离的CFAP43功能缺失变体。CFAP43编码纤毛和鞭毛相关蛋白，在睾丸中优先表达。最近的研究表明，由于精子鞭毛的形态异常，该基因的突变会导致男性不育。我们利用CRISPR/Cas9技术敲除了Cfap43小鼠，导致Cfap43缺陷小鼠表现为脑积水表型，并伴有运动纤毛的形态异常。结论CFAP43与导致NPH的脑纤毛形态或运动异常有关。
ObjectiveTo identify genes related to normal-pressure hydrocephalus (NPH) in one Japanese family with several members with NPH.MethodsWe 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.ResultsIn WES, we identified a loss-of-function variant in CFAP43 that segregated with the disease. CFAP43 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 Cfap43 using CRISPR/Cas9 technology, resulting in Cfap43-deficient mice that exhibited a hydrocephalus phenotype with morphologic abnormality of motile cilia.ConclusionOur results strongly suggest that CFAP43 is responsible for morphologic or movement abnormalities of cilia in the brain that result in NPH.