Nonsense mutation in <i>CFAP43</i> causes normal-pressure hydrocephalus with ciliary abnormalities.

Abstract

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 <i>CFAP43</i> that segregated with the disease. <i>CFAP43</i> 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 <i>Cfap43</i> using CRISPR/Cas9 technology, resulting in <i>Cfap43</i>-deficient mice that exhibited a hydrocephalus phenotype with morphologic abnormality of motile cilia. Our results strongly suggest that <i>CFAP43</i> is responsible for morphologic or movement abnormalities of cilia in the brain that result in NPH.