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WDR34 Deficiency Disrupts Retrograde Intraflagellar Transport and Induces Unfolded Protein Response-Driven
Bo Jia1,2,3, Jianan Xie1,2,3, Xuebin Zhou1,2,3
1Department of Ophthalmology, The Second Hospital of Jilin University, Changchun, China.
Investigative Ophthalmology & Visual Science
|August 4, 2026
Summary
WD repeat domain 34 (WDR34) deficiency causes retinal degeneration by impairing retrograde intraflagellar transport (IFT) in photoreceptor cells. This leads to unfolded protein response activation and inflammation, offering insights into RP therapies.
Area of Science:
- Ophthalmology
- Cell Biology
- Genetics
Background:
- Retinitis pigmentosa (RP) is an inherited condition causing progressive vision loss due to photoreceptor cell (PRC) degeneration.
- WD repeat domain 34 (WDR34) is vital for retrograde intraflagellar transport (IFT), but its role in RP is not fully understood.
Purpose of the Study:
- To investigate how WDR34 deficiency impacts retrograde IFT.
- To determine WDR34's contribution to retinal degeneration.
Main Methods:
- Modeled WDR34 deficiency in vivo using adeno-associated virus-shRNA-WDR34 and in vitro using CRISPR/Cas9.
- Assessed retinal degeneration and IFT defects via histologic, functional, and ultrastructural analyses.
- Utilized proteomic analysis and in vivo validation to explore molecular mechanisms.
Main Results:
- WDR34 knockdown resulted in progressive retinal degeneration, PRC apoptosis, and outer nuclear layer thinning.
- WDR34 deficiency impaired retrograde IFT, leading to mislocalization of rhodopsin and opsins.
- ER stress and unfolded protein response (UPR) activation occurred, involving the IRE1α/TRAF2/NF-κB pathway, contributing to inflammation and degeneration.
Conclusions:
- WDR34 is essential for maintaining retrograde IFT in PRCs.
- WDR34 deficiency disrupts photoreceptor outer segments, triggering UPR-mediated inflammation and apoptosis, leading to retinal degeneration.
- This study establishes a link between WDR34, IFT, ciliopathies, and RP, suggesting potential therapeutic targets.
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