RPE65

RPE65 is a gene that encodes an iron-dependent retinoid isomerohydrolase expressed in the retinal pigment epithelium (RPE). The RPE65 enzyme plays a key role in the visual cycle by converting all-trans-retinyl esters to 11-cis-retinol, a precursor of 11-cis-retinal, the light-sensitive chromophore used by cone and rod visual pigments. This isomerization step is essential for regenerating photopigments after light exposure.

Mutations in RPE65 cause autosomal recessive inherited retinal dystrophies, most notably Leber congenital amaurosis type 2 (LCA2) and other early-onset retinal dystrophies. Affected individuals typically present in infancy or early childhood with severe vision loss, nystagmus, and reduced light perception. Fundus findings are variable and may be normal early; dark adaptation is impaired and electroretinography is often reduced or extinguished.

RPE65 encodes a 533-amino-acid protein with a molecular mass around 65 kDa. The enzyme resides in the endoplasmic reticulum of the RPE and coordinates a metal cofactor, enabling isomerization of retinoids rather than hydrolysis. Loss of RPE65 disrupts 11-cis-retinal production, compromising phototransduction and leading to progressive retinal degeneration.

Therapy for RPE65-associated disease includes gene augmentation with voretigene neparvovec (Luxturna), an adeno-associated virus 2 (AAV2) vector delivering functional RPE65. It is approved for patients with biallelic pathogenic variants and sufficient remaining retinal cells, and has demonstrated improvements in functional vision and navigation in clinical trials. Research continues into alternative gene therapies, stem cell approaches, and pharmacologic strategies aimed at restoring the visual cycle.