Photoreceptor Sensory Cilium and Associated Disorders

Li, Linjing; Yildiz, Ozge; Anand, Manisha; Khanna, Hemant

doi:10.5772/48387

Cited by 2 publications

References 89 publications

(98 reference statements)

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Impaired glutamylation of RPGR ^ORF15 underlies the cone-dominated phenotype associated with truncating distal ORF15 variants

Cehajic-Kapetanovic

Cámara

Birtel

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Pathogenic variants in the Retinitis pigmentosa GTPase regulator (RPGR) gene lead to a clinically severe form of X-linked retinal dystrophy. However, it remains unclear why some variants cause a predominant rod, while others result in a cone-dominated phenotype. Post-translational glutamylation of the photoreceptor-specific RPGR ORF15 isoform by the TTLL5 enzyme is essential for its optimal function in photoreceptors, and loss of TTLL5 leads to retinal dystrophy with a cone phenotype. Here we show that RPGR retinal disease, studied in a single cohort of 116 male patients, leads to a clear progressive shift from rod- to cone-dominating phenotype as the RPGR ORF15 variant location approaches the distal part of the Open Reading Frame 15 (ORF15) region. The rod photoreceptor involvement on the contrary diminishes along the RGPR sequence, and the variants associated with the cone only phenotype are located predominantly in the very distal part, including the C-terminal basic domain. Moreover, these distal truncating RPGR ORF15 variants disrupt the interaction with TTLL5 and lead to a significant impairment of RPGR glutamylation. Thus, consistent with the phenotype of TTLL5 pathogenic variants, our study shows that RPGR ORF15 variants, which disrupt its basic domain and the interaction with TTLL5, also impair RPGR glutamylation and lead to the cone phenotype. This has implications for ongoing gene therapy clinical trials where the application of RPGR with impaired glutamylation may be less effective in treating RGPR dystrophies and may even convert a rod–cone dystrophy into a cone dystrophy phenotype.

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Impaired glutamylation of RPGR ^ORF15 underlies the cone-dominated phenotype associated with truncating distal ORF15 variants

Cehajic-Kapetanovic

Cámara

Birtel

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Retinal thermometry in-vivo using phase-sensitive optical coherence tomography

Zhuo,

Bhuckory,

et al. 2024

Preprint

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Controlling the tissue temperature rise during retinal laser therapy is essential for predictable outcomes, especially at non-damaging settings. We demonstrate a method for determining the temperature rise in the retina using phase-resolved optical coherence tomography (pOCT) in vivo. Measurements based on the thermally induced optical path length changes (ΔOPL) in the retina during a 10-ms laser pulse allow detection of the temperature rise with a precision less than 1 °C, which is sufficient for calibration of the laser power for patient-specific non-damaging therapy. We observed a significant difference in confinement of the retinal deformations between the normal and the degenerate retina: in wild-type rats, thermal deformations are localized between the retinal pigment epithelium (RPE) and the photoreceptors’ inner segments (IS), as opposed to a deep penetration of the deformations into the inner retinal layers in the degenerate retina. This implies the presence of a structural component within healthy photoreceptors that dampens the tissue expansion induced by the laser heating of the RPE and pigmented choroid. We hypothesize that the thin and soft cilium connecting the inner and outer segments (IS, OS) of photoreceptors may absorb the deformations of the OS and thereby preclude the tissue expansion further inward. Striking difference in the confinement of the retinal deformations induced by a laser pulse in healthy and degenerate retina may be used as a biomechanical diagnostic tool for the characterization of photoreceptor degeneration.

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Photoreceptor Sensory Cilium and Associated Disorders

Cited by 2 publications

References 89 publications

Impaired glutamylation of RPGR ^ORF15 underlies the cone-dominated phenotype associated with truncating distal ORF15 variants

Impaired glutamylation of RPGR ^ORF15 underlies the cone-dominated phenotype associated with truncating distal ORF15 variants

Retinal thermometry in-vivo using phase-sensitive optical coherence tomography

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Photoreceptor Sensory Cilium and Associated Disorders

Cited by 2 publications

References 89 publications

Impaired glutamylation of RPGR ORF15 underlies the cone-dominated phenotype associated with truncating distal ORF15 variants

Impaired glutamylation of RPGR ORF15 underlies the cone-dominated phenotype associated with truncating distal ORF15 variants

Retinal thermometry in-vivo using phase-sensitive optical coherence tomography

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Impaired glutamylation of RPGR ^ORF15 underlies the cone-dominated phenotype associated with truncating distal ORF15 variants

Impaired glutamylation of RPGR ^ORF15 underlies the cone-dominated phenotype associated with truncating distal ORF15 variants