RPE65 – Severe Early-Childhood-Onset Retinal Dystrophy

RPE65 encodes the retinal pigment epithelium-specific isomerohydrolase essential for the regeneration of 11-cis-retinol in the visual cycle. Biallelic loss-of-function or hypomorphic variants in RPE65 cause autosomal recessive severe early-childhood-onset retinal dystrophy, presenting in infancy with visual impairment and nyctalopia. The disorder follows an autosomal recessive inheritance pattern with compound heterozygous or homozygous variants required for disease manifestation.

Genetic analyses have identified multiple unrelated probands with RPE65-associated EOSRD: 10 patients with compound heterozygous or homozygous RPE65 mutations (PMID:15288992), 8 Indian patients with homozygous null alleles among 220 cases screened (PMID:38323530), and 46 probands detected in a cohort of 153 LCA/EOSRD patients by high-throughput array and sequencing (PMID:18055820). In a Chinese family, the patient harbored c.1590C>A (p.Phe530Leu) together with c.1243+2T>A, segregating in trans (PMID:25383945). Carriers are asymptomatic, consistent with recessive inheritance.

The RPE65 variant spectrum comprises >70 pathogenic alleles: missense substitutions (e.g., p.Arg91Trp, p.Tyr368His), loss-of-function changes including frameshifts and nonsense mutations, and splice-site defects like IVS1+5G>A. Recurrent alleles such as IVS1+5G>A have been observed across populations. Pathogenic allele frequency among LCA/EOSRD cohorts ranges from 3–16% (PMID:34281261).

Functional studies definitively establish RPE65 as the visual cycle isomerohydrolase. Recombinant RPE65 catalyzes conversion of all-trans-retinyl esters to 11-cis-retinol (PMID:16116091), and mutations of iron-coordinating residues or missense variants abolish activity (PMID:16150724). Rpe65–/– and knock-in mouse models recapitulate the human rod-cone dystrophy with absent autofluorescence, impaired electroretinograms, and photoreceptor loss (PMID:11528395, PMID:25972377).

Gene therapy and rescue experiments demonstrate therapeutic potential. Lentiviral or AAV-mediated Rpe65 gene transfer in knockout mice restores cone survival and ERG responses (PMID:17032058). In patients treated with voretigene neparvovec, OCT shows rapid morphological rescue of the fovea and improved central sensitivity (PMID:34289237). Chemical chaperones and low-temperature studies further rescue partial-function mutants (PMID:24849605).

Collectively, the robust genetic and experimental concordance fulfills ClinGen criteria for a Definitive gene–disease association. Early molecular diagnosis of RPE65 variants is critical for patient stratification and eligibility for gene replacement therapy.

Key Take-home: Biallelic pathogenic RPE65 variants reliably predict severe early-childhood-onset retinal dystrophy and identify candidates for effective gene augmentation therapy.

References

• PLoS one • 2014 • A novel mutation in the RPE65 gene causing Leber congenital amaurosis and its transcriptional expression in vitro. PMID:25383945
• Ophthalmology • 2004 • Lack of fundus autofluorescence to 488 nanometers from childhood on in patients with early-onset severe retinal dystrophy associated with mutations in RPE65. PMID:15288992
• Investigative ophthalmology & visual science • 2007 • An assessment of the apex microarray technology in genotyping patients with Leber congenital amaurosis and early-onset severe retinal dystrophy. PMID:18055820
• Ophthalmic genetics • 2024 • RPE65 mutations in Leber congenital amaurosis, early-onset severe retinal dystrophy, and retinitis pigmentosa from a tertiary eye care center in India. PMID:38323530
• International journal of molecular sciences • 2021 • Inherited Retinal Diseases Due to RPE65 Variants: From Genetic Diagnostic Management to Therapy. PMID:34281261
• Proceedings of the National Academy of Sciences of the United States of America • 2005 • RPE65 is the isomerohydrolase in the retinoid visual cycle. PMID:16116091
• Nature genetics • 2001 • New views on RPE65 deficiency: the rod system is the source of vision in a mouse model of Leber congenital amaurosis. PMID:11528395
• Human molecular genetics • 2015 • Mouse model of human RPE65 P25L hypomorph resembles wild type under normal light rearing but is fully resistant to acute light damage. PMID:25972377
• PLoS medicine • 2006 • Lentiviral gene transfer of RPE65 rescues survival and function of cones in a mouse model of Leber congenital amaurosis. PMID:17032058
• Acta ophthalmologica • 2022 • Short term morphological rescue of the fovea after gene therapy with voretigene neparvovec. PMID:34289237
• The Journal of biological chemistry • 2014 • Rescue of enzymatic function for disease-associated RPE65 proteins containing various missense mutations in non-active sites. PMID:24849605
• Human molecular genetics • 2008 • R91W mutation in Rpe65 leads to milder early-onset retinal dystrophy due to the generation of low levels of 11-cis-retinal. PMID:17933883

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