DOI: 10.1001/jamaophthalmol.2026.4692 ISSN: 2168-6165

Bi-Allelic PRKCZ Loss-of-Function Variants and Adult-Onset Retinitis Pigmentosa

Viviana Cordeddu, Riccardo Sangermano, Sterre W. M. Mulder, Hafiz Muhammad Jafar Hussain, Elisabetta Flex, Luca Mignini, Marialetizia Motta, Alessandro Bruselles, Maria Beatrice Arasi, Serena Cecchetti, Mattia Carvetta, Marcello Niceta, Antonella Lauri, Alessandro Leone, Graziamaria Paradisi, Puja A. Mehta, Li Yumei, Meng Wang, Wadih M. Zein, Stefanida Shliaga, Lonneke Haer Wigman, Yoeri van Leeuwen, Caroline C. W. Klaver, Ronald Pennings, L. Ingeborgh van den Born, Ayellet V. Segrè, Eric A. Pierce, Rob W. J. Collin, Carmen Dell’Aquila, Lucilla Barbano, Bin Guan, Emily M. Place, Siying Lin, Andrew R. Webster, Mariya Moosajee, Rui Chen, Gavin Arno, Susanne Roosing, Lucia Ziccardi, Kinga M. Bujakowska, Marco Tartaglia
Show PDF Cite

Importance

Inherited retinal diseases are genetically heterogeneous disorders, with retinitis pigmentosa (RP) representing the most common form; although more than 90 genes have been implicated, many RP cases remain molecularly unsolved.

Objectives

To describe an adult-onset RP phenotype associated with loss-of-function variants in PRKCZ , profile the clinical features of this disorder, and investigate the underlying disease mechanism.

Design, Setting, and Participants

In this case series study, genomic analyses were performed in individuals with unsolved childhood- and adult-onset retinal disease recruited through international research and diagnostic programs. Detailed clinical characterization was conducted in affected individuals. In vitro analyses were carried out to validate the genomic findings using primary and transduced cell-based experimental approaches. Genomic analyses were performed from October 2023 to December 2025; functional studies were carried out from January 2024 to May 2026.

Exposure

Bi-allelic likely pathogenic variants in a novel RP disease gene candidate, PRKCZ .

Main Outcomes and Measures

The primary outcome was genetic, clinical, and functional effects of bi-allelic PRKCZ inactivating variants associated with adult-onset RP. A detailed ophthalmologic assessment was conducted to characterize the clinical phenotype. Functional analyses in patient-derived fibroblasts and transduced cell lines were performed to validate the consequence of disruptive variants on PRKCZ transcript processing and PKCζ function.

Results

Among approximately 4500 individuals with unsolved childhood- and adult-onset retinal disease tested, 6 bi-allelic PRKCZ variants were identified in 13 affected individuals from 10 unrelated families, 5 of which were predicted to lead to loss of function (frameshift, nonsense, or splice-altering variants). Six of 13 affected individuals (46%) were female. Most cases carried a recurrent frameshift variant (c.139_140del; p.Met47Valfs*19). All variants selectively affected the long PRKCZ transcript encoding the N -terminal Phox and Bem1 (PB1) domain. Clinically, PRKCZ -associated RP showed adult onset (18-49 years), progressive night blindness, peripheral visual field constriction, and eventual central vision loss. Four individuals exhibited adult-onset sensorineural hearing loss. Functional studies in patient-derived fibroblasts demonstrated selective loss of the long PRKCZ isoform, impaired ciliogenesis, and altered mitochondrial organization, which were validated in stable PRKCZ knockdown cell lines. Structural modeling and coimmunoprecipitation assays indicated that the missense variant was associated with the disruption of PB1 domain–mediated protein-protein interactions.

Conclusions and Relevance

In this case series study, bi-allelic inactivating variants in PRKCZ were associated with adult-onset RP with an isoform-specific mechanism involving the long retinal-enriched transcript. These findings expand the genetic spectrum of RP and highlight PRKCZ as a potentially clinically relevant gene implicated in adult-onset retinal degeneration.

More from our Archive