Genetic mutations in retinol dehydrogenase 5 (RDH5) are associated with the inherited autosomal recessive retinal degeneration diseases, especially fundus albipunctatus (FA). Most of RDH5 mutants exhibit downregulation of RDH5 protein expression. However, the regulatory mechanism remains unclear. Here, we studied the metabolism of RDH5/L310delinsEV mutation, an indel mutation closely associated with the inherited FA disease. The half-life of RDH5/L310delinsEV was much less than RDH5/WT. Unlike RDH5/WT, which normally underwent degradation in autophagy-lysosomes, the RDH5/L310delinsEV reduced its location to the endoplasmic reticulum and was easy to be polyubiquitinated and degraded in the ubiquitin-proteasome pathway. Both RDH5/WT and RDH5/L310delinsEV interacted with autocrine motility factor receptor (AMFR), which is an E3 ligase on the endoplasmic reticulum. Overexpression of or knockdown of AMFR by siRNA increased or reduced the degradation of RDH5/L310delinsEV. The lysine 179 and lysine 263 of RDH5/L310delinsEV protein were polyubiquitination sites by AMFR. Mutation of K179R and K263R in RDH5/L310delinsEV protein reduced AMFR-mediated polyubiquitination and degradation. Taken together, these results highlight that RDH5/L310delinsEV mutant in RDH5 causes a rapid degradation in the ubiquitin-proteasome pathway. The fast degradation of RDH5/L310delinsEV may be associated with the FA development.

This case report discusses a diagnosis of fundus albipunctatus in a 12-year-old child who presented with diminution of vision at night in both eyes.

RPE65 is a key enzyme in the visual cycle, converting all-trans retinyl esters into 11-cis retinol, a crucial step in regenerating the photopigment necessary for vision. Mutations cause a spectrum of inherited retinal diseases (IRDs), from severe generalized early-onset dystrophies, such as Leber congenital amaurosis, to classical retinitis pigmentosa or mild phenotypes, including congenital stationary night blindness, such as fundus albipunctatus. We analyzed two independent patients with mild RPE65-associated IRDs using multimodal diagnostics, including best-corrected visual acuity; Goldman visual field; dark-adapted testing, including scotopic perimetry; full-field electroretinography; and multimodal retinal imaging. Phenotypes were evaluated based on existing literature and predicted variant impact. Both patients exhibited overall mild IRDs with only slightly impaired rod function and largely preserved cone function. Identified RPE65 missense variants likely allow partial enzyme function, consistent with comparatively mild and slowly progressive disease. Superior rod scotomas and mid-peripheral morphologic changes were identified despite normal or near-normal full-field function. Functional rod changes in the inferior mid-periphery of the retina, which may be followed by metabolic stress and structural retinal changes, seem to be the hallmark of mild RPE65-associated IRDs and may represent early site-specific pathology. These changes may be linked to an increased susceptibility to UV-induced retinal damage associated with RPE65 mutations. Local rod function assessment is critical for proper disease monitoring and guiding therapeutic decisions. Localized multimodal diagnostics help detect early changes in mild RPE65-associated IRDs, supporting precise monitoring and gene therapy counseling.

11-cis-retinal, the indispensable chromophore of photoreceptor opsins, is fundamental for light detection and the initiation of visual signal transduction. Its synthesis and regeneration through the visual cycle are critical not only for phototransduction but also for maintaining retinal homeostasis. Disruption of key enzymes, such as retinal pigment epithelium (RPE)65 and retinol dehydrogenases, results in toxic retinoid accumulation, oxidative stress, and progressive photoreceptor degeneration. These pathological mechanisms contribute to inherited and acquired retinal diseases, including Stargardt disease type 1, age-related macular degeneration, Leber congenital amaurosis, retinitis pigmentosa, and fundus albipunctatus. Recent therapeutic advances, ranging from gene replacement therapy with RPE65 (voretigene neparvovec, Luxturna®) to small-molecule modulators and antioxidant strategies, underscore the translational potential of targeting chromophore metabolism. This review outlines molecular processes underlying chromophore synthesis and regeneration, elucidates how disruptions in these processes contribute to inherited and acquired retinal pathologies, and evaluates existing and emerging therapeutic strategies that target chromophore metabolism. We highlight ongoing challenges and critical knowledge gaps to guide future investigations on basic science, translational research, and clinical practice. This review provides a comprehensive overview of the molecular mechanisms, current therapeutic approaches, and outstanding challenges, with a focus on future intervention directions.

Congenital stationary night blindness (CSNB) is a group of genetically and clinically heterogeneous non-progressive retinal disorders and can be classified based on fundus abnormalities as found in Oguchi disease or fundus albipunctatus (FA) or based on the absence of severe fundus abnormalities but altered electroretinography (ERG) findings. Here, we report the clinical and genetic findings of 46 CSNB families, with 18 families showing fundus abnormalities and 28 families without fundus abnormalities but having an altered ERG, showing complete CSNB (cCSNB) and Riggs type CSNB. Ophthalmic examinations including full-field ERG recordings, colour vision test, optical coherence tomography and fundus autofluorescence were performed and candidate genes for CSNB were screened by panel-based next-generation sequencing using an Illumina MiSeq platform. Subsequently, Sanger sequencing was performed to validate the identified variants and to confirm segregation with the phenotype in available family members. In 69% (11/16) of the Oguchi patients', pathogenic variants were found in SAG and GRK1, with p.(R292*) and p.(D537Vfs*7) variants being the most frequent mutations identified in this cohort in the two genes, respectively. A likely pathogenic variant p.(G238A) in RDH5 was identified in one of the two FA patients. In 92% of the CSNB (26/28) families without fundus abnormalities, pathogenic variants were found in NYX, leading to X-linked cCSNB; in GRM6, TRPM1, GPR179, LRIT3, leading to autosomal recessive cCSNB and in GNAT1, leading to autosomal recessive Riggs type CSNB. No significant copy number variants were identified. Combing this study with our previous report on CSNB from India, the most prevalent gene defects were variants in TRPM1 (37%) followed by GRM6 (32%) > NYX (10%) > SLC24A1 (5%) > GPR179 (5%), GNAT1 (3%) and LRIT3 (3%). In the current study, which included Oguchi disease and FA families as well, variants in SAG (38%) and GRK1 (31%) were identified in the Oguchi disease cases, and in the RDH5 gene in one of the two (50%) FA cases. Unsolved 8/56 (14%) (combined cohorts) cases may harbour variants in novel genes or intronic variants or structural variants undetectable by the screening method used herein.