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Primary ciliary dyskinesia (PCD) is a rare autosomal recessive disorder characterized by impaired ciliary motility that leads to chronic respiratory infections, sinusitis, bronchiectasis, and, in some cases, infertility. DNAAF3 has emerged as a critical gene in PCD pathogenesis, with multiple independent studies reporting biallelic mutations that disrupt the assembly of dynein arms, thereby impairing ciliary function (PMID:37537752).
Several case reports have identified DNAAF3 variants in affected individuals. For example, one study reported a novel homozygous mutation detected by whole‑exome sequencing in a patient with respiratory distress and infertility; subsequent Sanger sequencing confirmed segregation of the DNAAF3 variant in the family (PMID:37537752). Additionally, a separate report described a patient carrying a homozygous missense change with similar clinical manifestations, underscoring the gene’s contribution to variable PCD phenotypes.
Genetic evidence for DNAAF3 in PCD is further supported by multiple multi‑patient studies. These studies have identified diverse variant classes—including missense changes such as c.347T>A (p.Val116Glu)—across unrelated probands and families. Segregation analysis in these cohorts confirms that the DNAAF3 variants co‑segregate with the disease phenotype, reinforcing its role in the molecular etiology of PCD (PMID:31186518, PMID:35869935).
Functional and experimental assessments add another layer of validation. Investigations using transmission electron microscopy and immunostaining have shown a complete absence or severe reduction of outer dynein arms in patient samples with DNAAF3 mutations. Moreover, rescue experiments and CRISPR‑Cas9 models have recapitulated the key features of PCD, providing mechanistic insights into how DNAAF3 disruption contributes to ciliary dysfunction (PMID:37537752).
While some studies note variation in the clinical presentation of DNAAF3‑related PCD, the overall concordance between genetic findings and functional disruptions supports a robust gene–disease association. In particular, the reproducible demonstration of ciliary abnormalities across multiple independent cohorts underscores the clinical significance of DNAAF3 mutations in PCD.
Integrating genetic and functional data, the evidence indicates a strong relationship between DNAAF3 and primary ciliary dyskinesia. This comprehensive understanding supports the inclusion of DNAAF3 in diagnostic panels and underpins its potential utility in personalized treatment strategies. Key take‑home: DNAAF3 mutations are a critical determinant of PCD pathology, offering high clinical utility for accurate diagnosis and targeted therapy.
Gene–Disease AssociationStrongMultiple independent publications report DNAAF3 mutations in PCD patients with evidence from several case series (PMID:37537752, PMID:31186518) demonstrating consistent segregation, a diverse mutational spectrum, and functional disruption. Genetic EvidenceStrongSeveral studies identified homozygous and compound heterozygous DNAAF3 variants, including c.347T>A (p.Val116Glu), that co‑segregate with PCD phenotypes across unrelated families (PMID:31186518). Functional EvidenceModerateFunctional assays, including transmission electron microscopy and immunostaining, demonstrate that DNAAF3 mutations disrupt dynein arm assembly, leading to the characteristic ciliary defects observed in PCD (PMID:37537752). |