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

Area of Science:

• Genetics
• Neurology
• Cell Biology

Background:

• Normal-pressure hydrocephalus (NPH) is a neurological disorder characterized by impaired cerebrospinal fluid dynamics.
• The genetic underpinnings of NPH remain incompletely understood, necessitating further investigation into causative genes.

Purpose of the Study:

• To identify the genetic cause of normal-pressure hydrocephalus (NPH) in a Japanese family with multiple affected individuals.
• To investigate the role of the identified gene in the pathogenesis of hydrocephalus.

Main Methods:

• Whole-exome sequencing (WES) was performed on a Japanese family cohort with NPH.
• CRISPR/Cas9 gene editing was used to generate a knockout mouse model for the candidate gene.
• Phenotypic analysis of knockout mice, including assessment of cilia morphology and function.

Main Results:

• A loss-of-function variant in the Cilia And Flagella Associated Protein 43 (CFAP43) gene was identified and segregated with NPH in the family.
• CFAP43 is known to be involved in sperm flagella morphology and male infertility.
• CFAP43-deficient mice exhibited hydrocephalus and abnormal motile cilia in the brain, mirroring NPH phenotypes.

Conclusions:

• The study strongly implicates CFAP43 in the etiology of NPH.
• Defects in CFAP43 lead to morphologic or functional abnormalities of brain cilia, resulting in hydrocephalus.
• This research highlights the critical role of cilia in brain fluid homeostasis and NPH development.