PUBLICATION
PCYT1A Hypophosphorylation Underlies Retinal Lipid Dysregulation in CERKL Retinitis Pigmentosa and Is Therapeutically Reversed by Phosphatidylcholine
- Authors
- Gao, P., Li, P., Qin, Y., Hu, H., Reilly, J., Fu, Y., Wang, Q., Ren, M., Luo, J., Zhu, Y., Dai, L., Shu, X., Ren, X., Liu, F., Liu, M., Xu, C., Tang, Z.
- ID
- ZDB-PUB-260424-2
- Date
- 2026
- Source
- Investigative ophthalmology & visual science 67: 5454 (Journal)
- Registered Authors
- Liu, Fei, Liu, Mugen
- Keywords
- none
- MeSH Terms
- none
- PubMed
- 42023663 Full text @ Invest. Ophthalmol. Vis. Sci.
Citation
Gao, P., Li, P., Qin, Y., Hu, H., Reilly, J., Fu, Y., Wang, Q., Ren, M., Luo, J., Zhu, Y., Dai, L., Shu, X., Ren, X., Liu, F., Liu, M., Xu, C., Tang, Z. (2026) PCYT1A Hypophosphorylation Underlies Retinal Lipid Dysregulation in CERKL Retinitis Pigmentosa and Is Therapeutically Reversed by Phosphatidylcholine. Investigative ophthalmology & visual science. 67:5454.
Abstract
Purpose Retinitis pigmentosa (RP) is one of the main causes of hereditary blindness, and its genetic mode shows high heterogeneity. Among them, the mutation of the CERKL gene has been identified as the causative gene related to autosomal recessive hereditary RP. The underlying pathogenic mechanisms have remained obscure, hindering the development of effective therapies. This study aimed to elucidate the pathogenic mechanism linking CERKL deficiency to retinal degeneration and to identify a potential mechanism-based therapy.
Methods We used cerkl-/- zebrafish model, human retinal pigment epithelium (RPE)-1 cells, and utilized integrated multi-omics approaches (metabolomics, transcriptomics, and phosphoproteomics). Key findings were validated through lipid staining, biochemical assays, transmission electron microscopy (TEM), and rescue experiments.
Results CERKL deficiency triggered progressive lipid droplet (LD) accumulation in the RPE, associated with a profound reduction in phosphatidylcholine (PC) levels. Multi-omics integration revealed that PC deficiency stemmed from hypophosphorylation of the rate-limiting enzyme phosphate cytidylyltransferase 1A (PCYT1A) at a conserved serine residue (S331). Reconstitution of phosphomimetic PCYT1A (S331D) rescued LD pathology. Critically, exogenous PC supplementation alleviated LD accumulation, preserved photoreceptor outer segment structure, and improved retinal morphology in cerkl-/- zebrafish.
Conclusions Our work establishes dysregulated PC metabolism due to PCYT1A hypophosphorylation as a pathogenic driver in CERKL-deficient RP. We identify PC supplementation as a readily translatable, metabolic therapy for this genetically defined form of retinal degeneration.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping