CFAP43 – Normal-pressure Hydrocephalus

CFAP43 is an autosomal recessive gene encoding a cilia- and flagella-associated protein expressed in ependymal cells lining the ventricles. While mutations in CFAP43 were initially implicated in multiple morphological abnormalities of sperm flagella leading to male infertility, recent evidence has expanded the phenotypic spectrum to include normal-pressure hydrocephalus (NPH). NPH is characterized by ventricular enlargement with normal cerebrospinal fluid pressure, presenting clinically with gait disturbance, cognitive impairment, and urinary incontinence. Genetic heterogeneity in NPH has been increasingly recognized, with whole-exome and genome-wide studies implicating ciliary genes. Below is a summary of genetic and functional evidence supporting CFAP43 involvement in NPH.

In a Japanese family with autosomal recessive NPH, WES identified a homozygous loss-of-function CFAP43 variant c.4506G>A (p.Trp1502Ter) segregating in three affected individuals (PMID:31004071). No unaffected homozygotes were observed among siblings. The variant is predicted to trigger nonsense-mediated decay, leading to absence of functional protein. Detailed family studies showed complete penetrance in homozygotes and carrier asymptomatic status in heterozygotes. This autosomal recessive segregation supports a causal role for CFAP43 in NPH.

A systematic review of genetic risk factors in NPH reported enrichment of CFAP43 variants in NPH cohorts and identified over 30 familial cases, with 10–16% of patients having affected relatives (PMID:40266017). CFAP43 was one of several ciliary and blood–brain barrier genes implicated. The review encompassed genome-wide, exome, and CNV analyses across European populations. Despite methodological heterogeneity, the recurrent detection of CFAP43 variants underscores its contribution to NPH susceptibility. Protective variants near other genes also suggest complex genetic architecture. However, CFAP43 consistently emerged across studies.

CFAP43 encodes a cilia- and flagella-associated protein crucial for axonemal assembly and motility. It is preferentially expressed in testis and ependymal cells lining cerebral ventricles. Loss of CFAP43 disrupts motile cilia structure, impairing cerebrospinal fluid flow. This mechanistic link aligns with clinical features of NPH, including ventricular enlargement due to CSF accumulation. Moreover, parallels with male infertility phenotypes further support a common ciliary pathology. These insights position CFAP43 within the emerging category of ciliary genes underlying hydrocephalus disorders.

Functionally, CRISPR/Cas9-generated Cfap43 knockout mice developed hydrocephalus with abnormal ependymal cilia morphology, mirroring human NPH features (PMID:31004071). Histological analysis revealed dilated ventricles and disorganized ciliary bundles. These phenotypes confirm that CFAP43 deficiency suffices to induce hydrocephalus in vivo. In vitro, a c.3661-2del splice-site variant caused exon 30 skipping and predicted structural rearrangements in CFAP43 protein (PMID:32207550). Structural modelling demonstrated tighter protein conformation, likely disrupting axonemal interactions. Together, these assays provide functional concordance with genetic findings.

Collectively, biallelic CFAP43 loss-of-function variants cause NPH through defective ependymal ciliary motility, consistent across human genetics and animal models. The autosomal recessive inheritance and full penetrance in homozygotes support robust genotype–phenotype correlation. While additional loci may modify disease risk, CFAP43 emerges as a high-priority diagnostic gene in familial and sporadic NPH cases. Screening for CFAP43 variants can inform prognosis and management, including early intervention strategies. Future studies should explore therapeutic modulation of ciliary function. Key Take-home: CFAP43 LoF underlies autosomal recessive NPH via ciliary dysfunction, guiding genetic diagnosis and targeted research.

References

• Neurology • 2019 • Nonsense mutation in CFAP43 causes normal-pressure hydrocephalus with ciliary abnormalities. PMID:31004071
• Movement Disorders • 2025 • Genetic Risk Factors in Normal Pressure Hydrocephalus: What We Know and What Is Next. PMID:40266017
• Andrologia • 2020 • Mutational effect of human CFAP43 splice-site variant causing multiple morphological abnormalities of the sperm flagella. PMID:32207550

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