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RPE65
retinoid isomerohydrolase RPE65
The RPE65 gene provides instructions for producing a protein crucial for normal vision, playing a key role in the visual cycle within the retinal pigment epithelium. RPE65 encodes an enzyme vital for the visual cycle, a process that recycles light-sensitive molecules in the eye.
RPE65 is located on the short (p) arm of chromosome 1, at band 1p31.3. Arm ratio per GRCh38 - banding schematic.
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Overview
The RPE65 gene, also known as retinoid isomerohydrolase RPE65, is essential for maintaining healthy vision. It provides the genetic blueprint for a protein primarily active in the retinal pigment epithelium (RPE), a specialised cell layer at the back of the eye. This layer supports and nourishes the retina, the light-sensitive tissue responsible for detecting light and colour.
Dysfunction of the RPE65 protein, often due to pathogenic variants in the gene, is associated with inherited retinal diseases. These conditions can severely impair vision, often from early childhood.
What the gene does
The RPE65 protein functions as a crucial enzyme within the visual cycle, also known as the retinoid or vitamin A cycle. This complex biochemical pathway is responsible for recycling molecules within the retina after they have been exposed to light.
When light strikes the retina, a molecule called 11-cis retinal, a derivative of vitamin A, undergoes a transformation into all-trans retinal. This conversion initiates a cascade of chemical reactions, culminating in the generation of electrical signals that the brain interprets as vision. To enable continuous vision, the light-exposed molecules must be reset.
The RPE65 protein is indispensable for one of the critical steps in this recycling process. Specifically, it facilitates the conversion of all-trans retinyl ester into 11-cis retinol. Subsequently, other enzymes complete the cycle by transforming 11-cis retinol back into 11-cis retinal, making it ready to detect light again. Without a functional RPE65 protein, this recycling pathway is disrupted, leading to an accumulation of toxic intermediates and a deficiency of essential visual pigments, which profoundly affects retinal function.
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Chromosome location
The RPE65 gene is situated on the short arm of chromosome 1, at position 1p31.3. The human genome comprises 23 pairs of chromosomes, and chromosome 1 is one of the largest. The designation '1p31.3' refers to the specific band location on this chromosome, indicating its precise address within our genetic material. The gene encodes a protein consisting of 533 amino acids.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the RPE65 gene encompass a range of genetic changes that can affect the protein's function. These can include small changes in DNA building blocks (point mutations) or larger alterations. Pathogenic variants often lead to a non-functional or improperly functioning RPE65 protein, disrupting the visual cycle. The clinical impact of these variants varies, but they are generally associated with severe visual impairment.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
g.68429777_68449906del | - | Pathogenic | ★★★☆ | RPE65-related recessive retinopathy |
c.292_311del | p.Ile98Hisfs | Pathogenic | ★★★☆ | not provided |
c.1022T>C | p.Leu341Ser | Pathogenic | ★★★☆ | Retinitis pigmentosa 20 |
c.1059dup | p.Lys354fs | Pathogenic | ★★★☆ | Retinitis pigmentosa 20 |
c.1067del | p.Asn356fs | Pathogenic | ★★★☆ | Leber congenital amaurosis 2 |
c.1067dup | p.Asn356fs | Pathogenic | ★★★☆ | not provided |
c.106del | p.Leu36fs | Pathogenic | ★★★☆ | RPE65-related recessive retinopathy |
c.1084C>T | p.Gln362Ter | Pathogenic | ★★★☆ | Autism |
c.1087C>A | p.Pro363Thr | Pathogenic | ★★★☆ | Retinitis pigmentosa 20 |
c.10C>T | p.Gln4Ter | Pathogenic | ★★★☆ | Leber congenital amaurosis 2 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the RPE65 gene are primarily associated with inherited retinal dystrophies. The most notable condition linked to RPE65 is Leber congenital amaurosis (RPE65), a severe form of early-onset blindness. Other conditions, such as Fundus albipunctatus and certain forms of Retinitis pigmentosa, have also been associated with RPE65 variants.
- Leber congenital amaurosis (RPE65) Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic RPE65 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The RPE65 gene is recognised within the UK's genomic medicine initiatives. It is listed as a 'green' gene on the DDG2P (Deciphering Developmental Disorders) PanelApp, indicating strong evidence for its association with developmental disorders. Furthermore, RPE65 is a 'green' gene on the Retinal disorders panel (R32) in PanelApp, affirming its established role in inherited retinal conditions within the NHS Genomic Medicine Service.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Research into lifestyle factors for individuals with RPE65-related retinal conditions is ongoing. Generally, protecting eyes from excessive sunlight exposure, for example by wearing UV-protective sunglasses, is a common recommendation for individuals with retinal dystrophies. Maintaining a balanced diet rich in antioxidants and vitamins is often suggested for general eye health, though there is no conclusive evidence that specific dietary changes can prevent or reverse RPE65-related vision loss.
Supplement considerations
There is no conclusive evidence that specific dietary supplements can prevent or cure RPE65-related vision loss. While some supplements, such as vitamin A, are important for general eye health, caution is advised as excessive intake of certain vitamins can be harmful. Individuals considering supplements should consult a healthcare provider to discuss potential benefits and risks, especially if they have an inherited retinal dystrophy.
Frequently asked questions
What does the RPE65 gene do?
The RPE65 gene provides instructions for making a protein that is vital for the visual cycle, a process that recycles molecules in the retina after they've been exposed to light. This function is essential for normal vision.
What condition is most associated with RPE65 variants?
The RPE65 gene is most notably associated with Leber congenital amaurosis (RPE65), a severe inherited retinal dystrophy that typically causes profound vision loss from early childhood.
How is RPE65-related disease inherited?
RPE65-related conditions, such as Leber congenital amaurosis, are typically inherited in an autosomal recessive manner. This means an individual must inherit two copies of a pathogenic RPE65 variant (one from each parent) to develop the condition.
Can diet or lifestyle prevent RPE65-related vision loss?
Currently, there is no conclusive evidence that specific dietary changes or lifestyle interventions can prevent or cure RPE65-related vision loss. However, general eye protection and a balanced diet are often recommended for overall eye health.
Is the RPE65 gene included in UK genetic testing panels?
Yes, the RPE65 gene is recognised in UK genomic medicine and is listed as a 'green' gene on the DDG2P and Retinal disorders (R32) PanelApp, indicating its established clinical relevance for testing.
References
- Redmond TM. Focus on Molecules: RPE65, the visual cycle retinol isomerase. Experimental eye research. 2009. PMID: 18762184
- den Hollander AI, Roepman R, Koenekoop RK. Leber congenital amaurosis: genes, proteins and disease mechanisms. Progress in retinal and eye research. 2008. PMID: 18632300
- Redmond TM, Poliakov E, Yu S. Mutation of key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycle. Proceedings of the National Academy of Sciences of the United States of America. 2005. PMID: 16150724
- Thompson DA, Gyürüs P, Fleischer LL. Genetics and phenotypes of RPE65 mutations in inherited retinal degeneration. Investigative ophthalmology & visual science. 2000. PMID: 11095629
- Morimura H, Fishman GA, Grover SA. Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis. Proceedings of the National Academy of Sciences of the United States of America. 1998. PMID: 9501220