CCDC65 and Primary Ciliary Dyskinesia

Recent evidence supports an association between truncating variants in CCDC65 and primary ciliary dyskinesia, a disorder characterized by impaired ciliary motion despite normal ultrastructural appearance. The case report clearly identified a novel loss‑of‑function mutation that introduces a premature termination in CCDC65, correlating with a dyskinetic ciliary phenotype (PMID:23991085).

In a well‐documented family study, genetic linkage analysis pinpointed a single novel CCDC65 mutation segregating with disease, further establishing the gene’s role in the pathogenesis of primary ciliary dyskinesia. The consequences of the loss‑of‑function effect were corroborated by abnormal cilia beating patterns noted in both patient samples and gene‑silenced airway epithelial cells (PMID:23991085).

A multicenter investigation conducted in India further strengthened the genetic basis of this association. In a cohort of 67 patients with suspect primary ciliary dyskinesia, two definite cases were identified with deleterious CCDC65 variants among 29 confirmed PCD diagnoses (PMID:39004944). These observations underscore the clinical relevance of screening CCDC65 in patients who present with typical features of PCD despite normal ciliary ultrastructure.

The genetic evidence is further highlighted by the diversity of observed loss‑of‑function mutations. Among the reported variants, a representative mutation is c.699del (p.Asn232_Tyr233insTer), which exemplifies the type of truncating event disrupting normal protein function. This mutation, along with other similar variants, supports a model of autosomal recessive inheritance for CCDC65‑associated PCD.

Complementary functional studies provide additional support for this gene–disease relationship. Experimental models using both shRNA‑mediated silencing in human tracheobronchial epithelial cells and CRISPR‑induced disruption in zebrafish recapitulated the dyskinetic ciliary phenotype observed clinically, thus bolstering the argument for a causative role of CCDC65 deficiency (PMID:36533556).

In sum, the combined genetic and experimental data offer a coherent narrative that links loss‑of‑function mutations in CCDC65 to primary ciliary dyskinesia. This integrated evidence not only supports diagnostic decision‑making but also provides a robust foundation for future diagnostic panels and commercial genetic assays. Key take‑home: Assessing CCDC65 variants, such as c.699del (p.Asn232_Tyr233insTer), provides clinically actionable insights into PCD even in the absence of ultrastructural defects.

References

• PloS One • 2013 • CCDC65 mutation causes primary ciliary dyskinesia with normal ultrastructure and hyperkinetic cilia PMID:23991085
• Clinical Genetics • 2024 • Genetics of 67 patients of suspected primary ciliary dyskinesia from India PMID:39004944
• Disease Models & Mechanisms • 2022 • Variable phenotypes and penetrance between and within different zebrafish ciliary transition zone mutants PMID:36533556

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