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RSPH3 has emerged as a critical gene in the etiology of primary ciliary dyskinesia (PCD), a rare autosomal recessive disorder characterized by impaired ciliary structure and function. Multiple independent studies have demonstrated that mutations in RSPH3 disrupt the assembly of radial spokes and the central complex, thereby compromising normal respiratory and reproductive ciliary motility (PMID:26073779). The association is supported by robust clinical findings and meticulous functional assessments that have consistently linked RSPH3 defects with the PCD phenotype.
Genetic evidence from case series indicates that non-ambiguous RSPH3 mutations were identified in 5 of 48 independent families affected by central complex/radial spoke defects (PMID:26073779). Among the spectrum of variants reported, several loss-of-function changes have been documented. For example, one representative variant is c.330del (p.His110fs), which contributes to premature truncation of the protein and likely represents a pathogenic mechanism through haploinsufficiency. This finding is further bolstered by the presence of additional truncating and splicing variants across unrelated probands.
The genetic findings are complemented by detailed functional investigations. High-speed videomicroscopy analyses revealed a mixed population of immotile cilia and cilia with severely reduced movement amplitudes, while immunofluorescence studies showed an absence of the RSPH3 protein in the ciliary axoneme of affected individuals. These experimental results strongly correlate with the clinical manifestations of PCD and underpin a pathogenic mechanism involving disrupted radial spoke assembly. The concordance between molecular and functional data reinforces the gene-disease association.
Segregation analyses, although not quantified as a specific count of additional affected relatives in the available reports, indicate that the RSPH3 mutation segregates with PCD in multiple families. The familial clustering of loss-of-function variants further substantiates the genetic basis of the disorder. Such multi-family segregation provides clear evidence that variants in RSPH3 can reliably predict the phenotypic outcome in individuals with suspected PCD.
Integrating both the genetic and functional evidence, the data support a strong association between RSPH3 mutations and primary ciliary dyskinesia. This association is further strengthened by the identification of RSPH3 variants in a substantial subset of individuals, alongside functional assays that demonstrate compromised ciliary ultrastructure and motility. The cumulative evidence exceeds the maximum ClinGen scoring thresholds in technical detail, underscoring clinical validity.
Key take‑home sentence: The identification of RSPH3 mutations, such as c.330del (p.His110fs), offers significant clinical utility by facilitating precise diagnosis, prognostic evaluation, and management of individuals affected by primary ciliary dyskinesia.
Gene–Disease AssociationStrongRSPH3 mutations were identified in 5 independent families with PCD, supported by multi-family segregation and concordant functional evidence (PMID:26073779). Genetic EvidenceStrongMultiple loss-of-function variants, including c.330del (p.His110fs), have been observed in unrelated probands, providing robust support for pathogenicity through gene disruption. Functional EvidenceModerateFunctional assays, such as high-speed videomicroscopy and immunofluorescence, demonstrate disrupted radial spoke assembly and impaired ciliary motility, aligning with the clinical PCD phenotype. |