RPE65 – Leber congenital amaurosis type 2

Leber congenital amaurosis type 2 (LCA2) is a severe autosomal recessive retinal dystrophy characterized by early-childhood visual impairment, nyctalopia, and progressive vision loss. Patients present with markedly reduced or absent rod and cone electroretinographic responses and fundus changes including chorioretinal atrophy (PMID:11095629). The inheritance pattern is biallelic loss-of-function in RPE65, encoding the retinoid isomerohydrolase critical for 11-cis-retinol production in the visual cycle.

Genetic evidence for RPE65 in LCA2 includes a multi-patient study of 453 individuals with inherited retinal dystrophy identifying 20 probands harboring homozygous or compound heterozygous RPE65 variants, including missense, nonsense, splice, and frameshift alleles (PMID:11095629). Segregation analysis in a family with compound heterozygous c.1102T>C (p.Tyr368His) and IVS1+5G>A showed co-segregation in two affected siblings (PMID:11786058). Additional case reports document clinical course and morphological rescue after voretigene neparvovec therapy in adolescent and long-term follow-up patients (PMID:34289237; PMID:36225124). Collectively, these account for at least 24 unrelated probands with biallelic RPE65 variants.

The variant spectrum comprises >21 distinct pathogenic alleles, including missense changes such as c.1102T>C (p.Tyr368His), c.271C>T (p.Arg91Trp), and the recurrent splice-site variant c.643+5G>A. Frameshift and nonsense mutations, for example c.304G>T (p.Trp402Ter) and c.615_616del (p.Ile206fs), further support loss-of-function as the disease mechanism (PMID:11095629). Phenotypic variability correlates with residual enzymatic activity: hypomorphic alleles like c.74C>T (p.Pro25Leu) retain ~8% activity and present milder phenotypes (PMID:18599565).

Functional studies have established RPE65 as the isomerohydrolase catalyzing all-trans-retinyl esters to 11-cis-retinol. Recombinant RPE65 exhibits robust enzymatic activity requiring lecithin retinol acyltransferase (PMID:16116091), and site-directed mutagenesis of iron-coordinating residues abolishes this activity (PMID:16150724). Rpe65-/- mice lack 11-cis-retinal, exhibit absent rod responses, and their residual vision is cone-mediated until photoreceptor degeneration ensues (PMID:11528395). Gene therapy via lentiviral or AAV vectors restores RPE65 expression, rescues cone survival, and normalizes ERG patterns in animal models and human LCA2 patients (PMID:17032058; PMID:34289237).

No significant conflicting evidence disputes the RPE65–LCA2 association. Hypomorphic alleles clarify genotype–phenotype correlations but reinforce causality. The concordance across genetic cohorts, functional assays, and rescue experiments over >20 years supports a definitive gene–disease relationship.

Key Take-home: Biallelic loss-of-function variants in RPE65 cause definitive autosomal recessive LCA2, for which prompt molecular diagnosis enables eligibility for gene therapy with voretigene neparvovec.

References

• Investigative ophthalmology & visual science • 2000 • Genetics and phenotypes of RPE65 mutations in inherited retinal degeneration. PMID:11095629
• Archives of ophthalmology (Chicago, Ill. : 1960) • 2002 • Clinical course and visual function in a family with mutations in the RPE65 gene. PMID:11786058
• 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
• Proceedings of the National Academy of Sciences of the United States of America • 2005 • Mutation of key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycle. PMID:16150724
• 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
• 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
• Molecular genetics & genomic medicine • 2022 • Chorioretinal atrophy following voretigene neparvovec despite the presence of fundus autofluorescence. PMID:36225124

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