RPGR – Primary Ciliary Dyskinesia

The retinitis pigmentosa GTPase regulator (RPGR) gene, classically implicated in X-linked retinitis pigmentosa, has been increasingly reported in patients with primary ciliary dyskinesia (PCD), defining an X-linked recessive ciliopathy with both motile and photoreceptor cilia involvement. PCD cases harboring RPGR variants exhibit chronic respiratory infections, bronchiectasis, sinusitis, and male infertility, often accompanied by retinal degeneration features.

Genetic evidence includes five unrelated hemizygous male probands, each presenting with PCD and confirmed RPGR variants: a novel ORF15 splice–site deletion (c.1059_1059+2delGGT) in a 16-year-old with PCD and retinal thinning (PMID:30021045); a nonsense variant c.1234C>T (p.Arg412Ter) in an adult with bronchiectasis and RP (PMID:37915370); two brothers with c.309_310insA (p.Glu104ArgfsTer12) segregating with combined PCD and retinal dystrophy (PMID:38333087); and a missense c.920C>A (p.Thr307Lys) demonstrating co-segregation and carrier female phenotypes (PMID:38534367). Two pedigrees show familial segregation (PMID:30021045, PMID:38534367).

Functional assays reveal that RPGR mutations impair motile cilia biogenesis and orientation. Transmission electron microscopy and high-speed videomicroscopy of respiratory epithelium demonstrate intact ultrastructure but reduced ciliary beat coordination and disorganized alignment in carriers of c.154G>A(p.Gly52Arg) (PMID:22888088). In vitro transfection of nasal epithelial cells with mutant RPGR ORF15 variants shows failure of ciliary localisation and defective ciliogenesis (PMID:38534367).

Epidemiologically, RPGR contributes to a small fraction of PCD cases. It is identified in 1/41 Korean pediatric PCD patients (PMID:37957793) and in 1/29 genetically confirmed Indian PCD cases (PMID:39004944). A multicohort review underscores RPGR among rare PCD genes alongside DNAH11 and TXNDC3 (PMID:19410201).

Mechanistically, RPGR localises to basal bodies of both photoreceptor and motile cilia, interacting with dynein arm components and microtubule motors. Loss-of-function likely underlies X-linked PCD through disrupted ciliary cargo transport and axonemal function, analogous to its role in photoreceptor connecting cilia (PMID:16043481).

Despite limited cohort sizes, the consistent genetic and experimental findings support a Moderate ClinGen classification for the RPGR–PCD association. Additional larger studies and rescue experiments would strengthen this link.

Key take-home: RPGR genetic testing should be considered in male patients with unexplained PCD, especially when accompanied by retinal degeneration or family history of X-linked retinal disease.

References

• Ophthalmic Surg Lasers Imaging Retina • 2018 • Novel Mutation in Retinitis Pigmentosa GTPase Regulator Gene Causes Primary Ciliary Dyskinesia and Retinitis Pigmentosa PMID:30021045
• Respirology Case Reports • 2023 • X-linked inheritance of primary ciliary dyskinesia and retinitis pigmentosa due to RPGR variant: A case report and literature review PMID:37915370
• Frontiers in Pediatrics • 2024 • Identification of a novel RPGR mutation associated with retinitis pigmentosa and primary ciliary dyskinesia in a Slovak family: a case report PMID:38333087
• Cells • 2024 • Primary Ciliary Dyskinesia and Retinitis Pigmentosa: Novel RPGR Variant and Possible Modifier Gene PMID:38534367
• Pediatric Pulmonology • 2013 • RPGR mutations might cause reduced orientation of respiratory cilia PMID:22888088
• Paediatric Respiratory Reviews • 2009 • Ciliary defects and genetics of primary ciliary dyskinesia PMID:19410201

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