Rod-Cone Dystrophy Related WDR34 Is Essential for Ciliary Integrity and Survival of Mammalian Photoreceptor Cells

TL;DR

This study shows that WDR34 is crucial for the survival of photoreceptor cells in the retina and that its deficiency leads to retinal degeneration, which can be slowed with gene therapy.

Contribution

The study reveals the in vivo role of WDR34 in photoreceptor maintenance and demonstrates the therapeutic potential of WDR34 gene supplementation.

Findings

Wdr34 deficiency in rod photoreceptors causes progressive cell degeneration and reduced scotopic ERG responses.

Cone-specific Wdr34 ablation leads to impaired photopic ERG responses and cone cell death.

Gene therapy with WDR34 preserved photoreceptor structure and function in knockout mice.

Abstract

The photoreceptor outer segment is a highly specialized ciliary structure essential for phototransduction, rendering photoreceptors especially vulnerable to ciliary dysfunction. WDR34, a key component of the retrograde intraflagellar transport machinery, has been implicated in rod-cone dystrophy. However, the pathogenic mechanisms linking WDR34 deficiency to photoreceptor degeneration remain elusive. In this study we aim to investigate the in vivo function of Wdr34 in the photoreceptor cells using conditional knockout allele of Wdr34.

We generated retina-specific Wdr34 knockout mice using rod-specific and cone-specific drivers to investigate the in vivo roles of WDR34 in photoreceptor maintenance.

Wdr34 deficiency in rod photoreceptors resulted in progressive rod cell degeneration accompanied by a marked decline in scotopic electroretinography (ERG) responses. Similarly, cone-specific Wdr34 ablation led to impaired photopic ERG responses and subsequent cone photoreceptor death. Transcriptomic profiling of Wdr34-deficient retinas revealed broad differential gene expression changes, with significant enrichment in axonemal integrity and microtubule-based transport. Notably, subretinal delivery of an adeno-associated virus vector expressing WDR34 significantly preserved rod photoreceptor structure and function, underscoring the therapeutic potential of WDR34 gene supplementation.

Our findings establish WDR34 as a critical factor for photoreceptor survival and function, emphasizing its role in the pathogenesis of WDR34-associated retinal degeneration. Moreover, this study demonstrates that WDR34-targeted gene therapy can effectively delay photoreceptor loss, highlighting a promising treatment strategy for patients with WDR34-related retinal disease.

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