Nonsense mutation in CFAP43 causes normal-pressure hydrocephalus with ciliary abnormalities

Neurology. 2019 May 14;92(20):e2364-e2374. doi: 10.1212/WNL.0000000000007505.

Yoshiro Morimoto ¹, Shintaro Yoshida ¹, Akira Kinoshita ¹, Chisei Satoh ¹, Hiroyuki Mishima ¹, Naohiro Yamaguchi ¹, Katsuya Matsuda ¹, Miako Sakaguchi ¹, Takeshi Tanaka ¹, Yoshihiro Komohara ¹, Akira Imamura ¹, Hiroki Ozawa ¹, Masahiro Nakashima ¹, Naohiro Kurotaki ¹, Tatsuya Kishino ¹, Koh-Ichiro Yoshiura ¹, Shinji Ono ²

Affiliations

1 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.
2 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. [email protected].

PMID: 31004071 DOI: 10.1212/WNL.0000000000007505

Abstract

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 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.

Conclusion: Our results strongly suggest that CFAP43 is responsible for morphologic or movement abnormalities of cilia in the brain that result in NPH.

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