Retinal Phd2 ablation partially rescues Crb1Crb2-associated Leber congenital amaurosis and alters metabolic signaling
- 1LUMC
Abstract
Leber congenital amaurosis (LCA) is a severe early-onset retinal dystrophy caused by pathogenic variants in several genes, including CRB1. CRB1-associated LCA is characterized by disrupted retinal polarity, lamination, and photoreceptor organization, with no restorative treatment. We investigated whether retinal deletion of Phd2 (Egln1), encoding prolyl hydroxylase domain protein 2 (PHD2), could provide mutation-independent neuroprotection in a severe developmental model of CRB1-associated LCA. Using conditional Crb1/Crb2-deficient mice, we additionally deleted Phd2 throughout the neural retina and assessed retinal function, structure, visually guided behavior, and glycolysis-associated gene and protein expression at one and two months. Compared with Crb1/Crb2-deficient mice, additional Phd2 deletion partially improved scotopic responses and significantly increased the optomotor spatial-frequency threshold, whereas b-wave and cone-mediated responses remained impaired. Phd2Crb1Crb2-deficient retinas displayed more organized photoreceptor rosettes containing rod- and cone-marker-positive cells, in contrast to the diffuse outer-retinal disorganization and nuclear-layer amalgamation observed in Crb1/Crb2-deficient retinas. Polarity- and synapse-associated proteins showed improved local compartmentalization within these structures. Metabolic responses were temporally selective: Glut1 and Vegfa transcript levels increased at one month, whereas GLUT1 and LDHA protein levels increased at two months; Pdk1 transcript levels decreased at 2M, whereas PDK1 protein abundance remained unchanged. Although Phd2 deletion did not correct the underlying Crumbs-complex defect or normalize retinal lamination, and elevated Vegfa coincided with persistent vascular abnormalities, these findings demonstrate that retinal Phd2 deletion partially modifies the structural and functional consequences of severe Crb1/Crb2 deficiency and supports further investigation of PHD2-associated metabolic signaling as a potential disease-modifying target for severe CRB1-associated retinal degeneration.
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BibTeX
@misc{karthikeyan2026retinal,
title = {{Retinal Phd2 ablation partially rescues Crb1Crb2-associated Leber congenital amaurosis and alters metabolic signaling}},
author = {V. Karthikeyan and C. A. Andriessen and A. Peeters and X. Lu and A. A. Mulder and Z. Hosseinzadeh and R. I. Koning and J. Wijnholds},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.26.761799},
url = {https://www.biorxiv.org/content/10.64898/2026.10.26.761799v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Retinal Phd2 ablation partially rescues Crb1Crb2-associated Leber congenital amaurosis and alters metabolic signaling
AU - V. Karthikeyan
AU - C. A. Andriessen
AU - A. Peeters
AU - X. Lu
AU - A. A. Mulder
AU - Z. Hosseinzadeh
AU - R. I. Koning
AU - J. Wijnholds
PY - 2026
DA - 2026/10/26
PB - bioRxiv
DO - 10.64898/2026.10.26.761799
UR - https://www.biorxiv.org/content/10.64898/2026.10.26.761799v1
AB - Leber congenital amaurosis (LCA) is a severe early-onset retinal dystrophy caused by pathogenic variants in several genes, including CRB1. CRB1-associated LCA is characterized by disrupted retinal polarity, lamination, and photoreceptor organization, with no restorative treatment. We investigated whether retinal deletion of Phd2 (Egln1), encoding prolyl hydroxylase domain protein 2 (PHD2), could provide mutation-independent neuroprotection in a severe developmental model of CRB1-associated LCA. Using conditional Crb1/Crb2-deficient mice, we additionally deleted Phd2 throughout the neural retina and assessed retinal function, structure, visually guided behavior, and glycolysis-associated gene and protein expression at one and two months. Compared with Crb1/Crb2-deficient mice, additional Phd2 deletion partially improved scotopic responses and significantly increased the optomotor spatial-frequency threshold, whereas b-wave and cone-mediated responses remained impaired. Phd2Crb1Crb2-deficient retinas displayed more organized photoreceptor rosettes containing rod- and cone-marker-positive cells, in contrast to the diffuse outer-retinal disorganization and nuclear-layer amalgamation observed in Crb1/Crb2-deficient retinas. Polarity- and synapse-associated proteins showed improved local compartmentalization within these structures. Metabolic responses were temporally selective: Glut1 and Vegfa transcript levels increased at one month, whereas GLUT1 and LDHA protein levels increased at two months; Pdk1 transcript levels decreased at 2M, whereas PDK1 protein abundance remained unchanged. Although Phd2 deletion did not correct the underlying Crumbs-complex defect or normalize retinal lamination, and elevated Vegfa coincided with persistent vascular abnormalities, these findings demonstrate that retinal Phd2 deletion partially modifies the structural and functional consequences of severe Crb1/Crb2 deficiency and supports further investigation of PHD2-associated metabolic signaling as a potential disease-modifying target for severe CRB1-associated retinal degeneration.
ER -