RDH5 — Retinol dehydrogenase 5

The RDH5 gene acts like an instruction manual for making an important protein in your eyes called 11-cis retinol dehydrogenase 5. This protein works in a layer of cells at the back of your eye to help recycle vitamin A, which your eyes need to detect light and send visual signals to your brain. It is especially important for helping you see in the dark or in low-light conditions. When there is a mutation or error in the RDH5 gene, your eyes cannot produce enough of this working protein. As a result, the recycling process slows down, and your eyes struggle to adjust to the dark, leading to a condition called night blindness. The un-recycled vitamin A can also build up and form tiny yellowish-white spots on your retina, which is a hallmark of a condition called fundus albipunctatus. While this condition mainly affects night vision, some people may also experience problems with their central vision or color vision as they get older.

Gene description: The RDH5 gene provides instructions for making the enzyme 11-cis retinol dehydrogenase 5, which is essential for normal vision, particularly in low-light conditions. Mutations in this gene disrupt the visual cycle, leading to inherited retinal diseases such as fundus albipunctatus, characterized by impaired night vision and retinal flecks.

Patient and family guide: The RDH5 gene acts like an instruction manual for making an important protein in your eyes called 11-cis retinol dehydrogenase 5. This protein works in a layer of cells at the back of your eye to help recycle vitamin A, which your eyes need to detect light and send visual signals to your brain. It is especially important for helping you see in the dark or in low-light conditions. When there is a mutation or error in the RDH5 gene, your eyes cannot produce enough of this working protein. As a result, the recycling process slows down, and your eyes struggle to adjust to the dark, leading to a condition called night blindness. The un-recycled vitamin A can also build up and form tiny yellowish-white spots on your retina, which is a hallmark of a condition called fundus albipunctatus. While this condition mainly affects night vision, some people may also experience problems with their central vision or color vision as they get older.

Gene function: The RDH5 gene encodes the enzyme 11-cis retinol dehydrogenase 5, which is predominantly expressed in the retinal pigment epithelium. This enzyme plays a crucial role in the visual cycle by catalyzing the conversion of 11-cis retinol to 11-cis retinal, a molecule necessary for the formation of photosensitive pigments in photoreceptors.

Protein structure: RDH5 is a 318-amino acid membrane-associated protein belonging to the short-chain dehydrogenases/reductases (SDR) family. It forms a complex with other membrane proteins in the retinal pigment epithelium and its stability is regulated by interacting with HSP90.

Molecular function: RDH5 functions as a short-chain dehydrogenase/reductase that catalyzes the final step in the biosynthesis of 11-cis retinaldehyde. Specifically, it performs the NAD-dependent oxidation of cis-isomers of retinol, including 11-cis-, 9-cis-, and 13-cis-retinol, converting them into their corresponding retinal forms. This process is essential for regenerating the visual chromophore needed by both rod and cone photoreceptors to detect light.

Mutation spectrum: Over 60 mutations have been identified in the RDH5 gene, including missense, nonsense, small deletions, small insertions/duplications, small indels, and splicing substitutions. Missense and nonsense mutations are the most common types observed in patients with fundus albipunctatus.

Clinical significance: Mutations in the RDH5 gene reduce or eliminate the function of the 11-cis retinol dehydrogenase 5 enzyme, leading to a shortage of 11-cis retinal. This impairs the visual cycle, preventing the normal conversion of light into electrical signals, which causes night blindness. It also leads to the accumulation of 11-cis retinol and related molecules, forming the characteristic whitish-yellow flecks in the retina seen in fundus albipunctatus. In some cases, it can progress to macular atrophy and cone dystrophy.

Inheritance: Autosomal Recessive

Chromosomal location: 12q13.2

Research and therapeutic approaches: Currently, there are no FDA-approved gene therapies specifically for RDH5 mutations. However, gene therapy approaches using adeno-associated virus (AAV) vectors to deliver healthy copies of the RDH5 gene to the retinal pigment epithelium are being explored in preclinical studies and animal models as a potential treatment to restore the visual cycle.