Nonsense mutation in causes normal-pressure hydrocephalus with ciliary abnormalities.

Neurology 2019 May 19;92(20):e2364-e2374. Epub 2019 Apr 19.

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.

Objective: To identify genes related to normal-pressure hydrocephalus (NPH) in one Japanese family with several members with NPH.

Methods: 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.

Results: 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.

Conclusion: Our results strongly suggest that is responsible for morphologic or movement abnormalities of cilia in the brain that result in NPH.

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000007505DOI Listing

Still can't find the full text of the article?

We can help you send a request to the authors directly.
May 2019
11 Reads

Publication Analysis

Top Keywords

normal-pressure hydrocephalus
8
japanese family
8
candidate gene
8
loss-of-function variant
4
variant segregated
4
morphologic abnormality
4
phenotype morphologic
4
identified loss-of-function
4
hydrocephalus phenotype
4
encoding cilia-
4
disease encoding
4
wes identified
4
segregated disease
4
pathogenesis hydrocephalusresults
4
motile ciliaconclusion
4
mouse crispr/cas9
4
flagella knocked
4
generated knockout
4
crispr/cas9 confirm
4
confirm candidate
4

Altmetric Statistics

Similar Publications