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

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.

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Journal
JAMA Ophthalmology
Published
2026-10-29
DOI
https://doi.org/10.1001/jamaophthalmol.2026.4692
Primary Topic
Retinal Development and Disorders
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article

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

Mattia Carvetta, Kinga M. Bujakowska, Riccardo Sangermano, Marcello Niceta et al.
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JAMA Ophthalmology
Retinal Development and Disorders
article

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

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

Abstract

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.

JAMA Ophthalmology
Broad Institute (US), Massachusetts Eye and Ear Infirmary (US), University of Molise (IT), National Institutes of Health (US), Moorfields Eye Hospital NHS Foundation Trust (GB), Harvard University (US), Baylor College of Medicine (US), University of California, Irvine (US), Istituto Superiore di Sanità (IT), The Francis Crick Institute (GB), Manchester Royal Eye Hospital (GB), Erasmus MC (NL), Radboud University Medical Center (NL), University of Manchester (GB), NIHR Moorfields Biomedical Research Centre (GB), Manchester University NHS Foundation Trust (GB), Fondazione G.B. Bietti (IT), Rotterdam Eye Hospital (NL), Bambino Gesù Children's Hospital (IT), National Eye Institute (US), Greenwood Genetic Center (US), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Institute of Molecular and Clinical Ophthalmology Basel (CH), Donders Institute for Brain, Cognition and Behaviour (NL), University College London (GB), Sapienza University of Rome (IT)
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Retinal Development and Disorders
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