HGNC Approved Gene Symbol: RPE65
Cytogenetic location: 1p31.3 Genomic coordinates (GRCh38): 1:68,428,822-68,449,954 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p31.3 | Leber congenital amaurosis 2 | 204100 | Autosomal recessive | 3 |
| Retinitis pigmentosa 20 | 613794 | Autosomal recessive | 3 | |
| Retinitis pigmentosa 87 with choroidal involvement | 618697 | Autosomal dominant | 3 |
The RPE65 protein is the source of isomerohydrolase activity (conversion of all-trans retinyl ester to 11-cis retinol) in the retinal pigment epithelium (summary by Moiseyev et al., 2005).
The retinal pigment epithelium (RPE) is a monolayer simple epithelium apposed to the outer surface of the retinal photoreceptor cells. It is involved in many aspects of outer retinal metabolism that are essential to the continued maintenance of the photoreceptor cells, including many RPE-specific functions such as the retinoid visual cycle and photoreceptor outer segment disc phagocytosis and recycling. Hamel et al. (1993) characterized and cloned a unique RPE-specific microsomal protein, RPE65, that is conserved in vertebrates and was a candidate for the site of mutation in hereditary retinal disorders implicating the RPE.
Nicoletti et al. (1995) characterized the RPE65 gene, which encodes the abundant 61-kD protein in retinal pigment epithelium. They stated that this was the first structural characterization of a gene transcribed specifically in the RPE. Nicoletti et al. (1995) identified a single RPE65 transcript of approximately 2.9 kb that was present in human retinal pigment epithelium and was not detected in other tissues. The deduced 533-amino acid sequence of the human protein is 98.7% similar to the bovine protein. Expression of the protein appears to depend on the presence of environmental cues, since the corresponding transcripts are rapidly lost from RPE cells established in culture. Nicoletti et al. (1995) suggested that downregulation may occur posttranscriptionally, since AU-rich elements proposed to target RNA for rapid degradation are present throughout the 3-prime untranslated region. The tissue-specific expression, high abundance, evolutionary conservation, developmental regulation, and sequence of the 3-prime untranslated region suggested that the 61-kD protein is the product of a functionally important gene whose expression is tightly regulated. Bavik et al. (1992) proposed that the protein acts as the receptor for retinol-binding protein on the surface of the retinal pigment epithelium.
Nicoletti et al. (1995) determined that the RPE65 gene contains 14 coding exons spanning 20 kb.
Using a human/hamster hybrid panel, Hamel et al. (1994) mapped the human RPE65 gene to chromosome 1 and, by fluorescence in situ hybridization, refined the localization to chromosome 1p31. By study of rodent/human somatic cell hybrids and by fluorescence in situ hybridization, Nicoletti et al. (1995) confirmed the assignment to chromosome 1p31.
Using interspecific backcross analysis, Hamel et al. (1994) mapped the mouse Rpe65 gene to the distal portion of chromosome 3.
Xue et al. (2004) showed that the membrane-associated form of RPE65 (mRPE65) is triply palmitoylated and is a chaperone for all-trans-retinyl esters, allowing their entry into the visual cycle for processing into 11-cis-retinal. The soluble form of RPE65 (sRPE65) is not palmitoylated and is a chaperone for vitamin A rather than all-trans-retinyl esters. Thus, the palmitoylation of RPE65 controls its ligand binding selectivity. The 2 chaperones are interconverted by lecithin retinol acyltransferase (LRAT; 604863) acting as a molecular switch, with mRPE65 as the palmitoyl donor. When chromophore synthesis is not required, mRPE65 is converted into sRPE65 by LRAT, and further chromophore synthesis is blocked. The studies revealed novel roles for palmitoylated proteins as molecular switches and for LRAT as a palmitoyl transferase whose role is to catalyze the conversion of mRPE65 to sRPE65.
Within the visual cycle, an isomerohydrolase is responsible for isomerization and hydrolysis of all-trans retinyl ester to 11-cis retinol, and LRAT provides the retinyl ester substrate. Moiseyev et al. (2005) found that recombinant human RPE65, when coexpressed with LRAT in human embryonic kidney cells or COS-1 cells, efficiently generated 11-cis retinol from all-trans retinyl ester. Enzymatic activity was linearly dependent on the expression level of RPE65. Moiseyev et al. (2005) concluded that RPE65 is the isomerohydrolase of the retinal visual cycle.
Moiseyev et al. (2006) found that deprivation of metal ions from bovine RPE microsomes through treatment with metal chelators inhibited Rpe65 isomerohydrolase activity. Addition of Fe(2+) restored the activity in a concentration-dependent manner, demonstrating that RPE65 is an Fe(2+)-dependent isomerohydrolase in the retinoid visual cycle.
By RNA-sequencing analysis of chicken embryonic RPE/choroid total RNA, Shyam et al. (2017) found that expression of Rpe65 drastically increased during production of meso-zeaxanthin, an ocular-specific carotenoid with no common dietary source. Overexpression of RPE65 in HEK293T cells showed that RPE65 catalyzed conversion of lutein to meso-zeaxanthin. RPE primary cultures from chicken embryos retained Rpe65 expression and produced meso-zeaxanthin upon lutein treatment. Pharmacologic inhibition of Rpe65 activity specifically blocked meso-zeaxanthin production in the developing chicken embryos. Using structural docking analysis, the authors found that the epsilon ring of lutein molecules fit into the active site of a homology model for chicken Rpe65.
Leber Congenital Amaurosis 2 and Retinitis Pigmentosa 20
By SSCP analysis of PCR-derived genomic DNA, in 2 sibs with Leber congenital amaurosis (LCA2; 204100), Marlhens et al. (1997) identified compound heterozygosity for mutations in the RPE65 gene: a 1067delA mutation (180069.0001) and an R234X mutation (180069.0002) inherited from the mother and father, respectively.
Autosomal recessive childhood-onset severe retinal dystrophy is a heterogeneous group of disorders affecting rod and cone photoreceptors simultaneously. The most severe cases are termed Leber congenital amaurosis (see 204000), whereas the less aggressive forms are usually considered juvenile retinitis pigmentosa. Disease genes implicated in other forms of autosomal recessive childhood-onset severe retinal dystrophy are expected to encode proteins present in the neuroretina or in the retinal pigment epithelium. Gu et al. (1997) analyzed RPE65 in a collection of about 100 unselected patients of different ethnic origins with severe retinal dystrophy and found 5 presumably pathogenic mutations, including a missense mutation (P363T; 180069.0003), 2 point mutations affecting splicing, and 2 small rearrangements on a total of 9 alleles of 5 patients from India and Germany with this phenotype. In contrast to other genes whose defects have been implicated in degenerative retinopathies, RPE65 is the first disease gene in this group of inherited disorders that is expressed exclusively in the RPE and may play a role in vitamin A metabolism of the retina. Gu et al. (1997) estimated that RPE65 mutations account for approximately 5% of autosomal recessive childhood-onset severe retinal dystrophy.
Morimura et al. (1998) examined all 14 exons of the RPE65 gene in 147 unrelated patients with autosomal recessive retinitis pigmentosa, 15 patients with isolated RP, and 45 patients with Leber congenital amaurosis. Sequence anomalies that were likely to be pathogenic were found in 2 patients with recessive RP, 1 patient with isolated RP recategorized as recessive, and 7 patients with LCA. Cosegregation analysis in each available family showed that all affected individuals were either homozygotes or compound heterozygotes and that all unaffected individuals were either heterozygote carriers or homozygous wildtype. In 1 family, there was 1 instance of a new mutation not present in either parent of the affected individual. In another family, affected members with recessive RP in 3 branches (i.e., 3 distinct pairs of parents) were compound heterozygotes for the same 2 mutations or homozygous for 1 of them. Based on their results, Morimura et al. (1998) estimated that mutations in the RPE65 gene account for approximately 2% of cases of recessive RP and approximately 16% of cases of LCA. In light of these findings, the clinical criteria distinguishing RP from LCA deserve special attention. RP is diagnosed in patients with photoreceptor degeneration who have good central vision within the first decade of life, and the diagnosis of LCA is given to patients who are born blind or lose vision within a few months after birth. Both diagnostic entities feature attenuated retinal vessels and a variable amount of retinal pigmentation in older patients and a reduced or nondetectable electroretinogram (ERG) at all ages. Both, furthermore, exhibit nonallelic heterogeneity. LCA is almost always recessively inherited, whereas families with RP can show any of the commonly recognized mendelian inheritance patterns or maternal (mitochondrial) or digenic inheritance. There is no universally accepted diagnostic term for those patients with retinal degeneration who lose useful (i.e., ambulatory) vision during the first few years of life; some ophthalmologists consider such cases to be LCA and others, severe RP. Morimura et al. (1998) observed an affected family (their family 0748) in which a child with LCA was the offspring of 2 parents with RP. Although the 2 parents did not participate in the study, the authors speculated that they were compound heterozygotes due to compound heterozygosity including the mutation found in the child. The child was homozygous for an intron 6 A-to-T transversion at position -2 in the splice acceptor site.
Thompson et al. (2002) reported the first 2 cases of uniparental disomy resulting in retinal degeneration. One patient had an apparently homozygous loss-of-function mutation of the RPE65 gene (Thompson et al., 2000); the other patient was apparently homozygous for a loss-of-function mutation of the MERTK gene (604705.0002), located on chromosome 2q14.1. In both families, the gene defect was present in the patient's heterozygous father but not in the patient's mother. Analysis of haplotypes in each nuclear kindred, by use of DNA polymorphisms distributed along both chromosome arms, indicated the absence of the maternal allele for all informative markers tested on chromosome 1 in the first patient and on chromosome 2 in the second patient. Thompson et al. (2002) interpreted the findings as indicating that retinal degeneration in these individuals was due to complete paternal isodisomy involving reduction to homoallelism for the mutated allele in each case. The findings provided evidence for the first time, in the case of chromosome 2, and confirmed previous observations, in the case of chromosome 1, that there are no paternally imprinted genes on chromosomes 1 and 2 that have a major effect on phenotype.
Felius et al. (2002) reported the phenotype and clinical course of affected and carrier members of a family with 2 RPE65 mutations present in compound heterozygous form: a missense mutation (Y368H; 180069.0009) and a splice site mutation (IVS+5G-A; 180069.0010). The affected brothers had severe visual compromise in childhood that progressed to nearly total visual loss by the second to third decade of life. The retinal and functional changes in the father who carried a presumed functional and a null allele suggested to the authors that some RPE65 heterozygous carriers may manifest visual symptoms.
In 13 patients with early-onset severe retinal dystrophy (LCA2; 204100) from 9 related Dutch families from a genetically isolated population living on a former island, Yzer et al. (2003) analyzed the RPE65 gene and identified homozygosity for the Y368H mutation. A patient from another related family was found to be compound heterozygous for Y368H and the IVS1+5G-A splice site mutation. Among 25 unaffected sibs tested, 17 were heterozygous for the Y368H mutation, and the Y368H mutation was also found in 3 (3.1%) of 96 unrelated controls from the same isolated population. Yzer et al. (2003) stated that the Y368H mutation most likely represented a founder mutation inherited from a common ancestor of all 10 Dutch families who was born in the 18th century or earlier.
Using Western blot analysis with transfected human cells, Chen et al. (2006) showed that point mutations in RPE65 associated with LCA2, including P363T, decreased RPE65 protein levels, but not mRNA levels, due to decreased stability of the mutant proteins. The mutations also abolished RPE65 enzymatic activity. Whereas wildtype RPE65 localized in ER and plasma membranes, the mutants localized mainly in the plasma membrane.
Retinitis Pigmentosa 87 with Choroidal Involvement
In 20 affected members of a large 4-generation Irish family segregating autosomal dominant retinitis pigmentosa with choroidal involvement that mapped to chromosome 1p31 (RP87; 618697), Bowne et al. (2011) identified heterozygosity for a missense mutation in the RPE65 gene (D477G; 180069.0013). The mutation was also detected in 4 unaffected family members, indicating incomplete penetrance. Screening for the D477G mutation in 12 Irish patients with a range of inherited retinal degenerations identified a man diagnosed with choroideremia (see 303100) who carried the D477G variant, which was also found in his 2 affected daughters. The mutation was shown to have occurred on the same haplotype as in the original family, and the authors stated that the clinical phenotype in the second family was consistent with that of the first family.
In 5 affected individuals from 2 families of Irish ancestry with autosomal dominant retinal dystrophy phenotypes, Hull et al. (2016) identified the RPE65 D477G mutation. The authors noted that 4 of the 5 affected individuals exhibited severe disease resembling choroideremia, with much more extensive RPE and choroidal degeneration than retinal degeneration, although ERGs showed a rod-cone pattern of photoreceptor degeneration. In contrast, the fifth patient presented with adult-onset vitelliform macular dystrophy (see 153840), which the authors suggested might be unrelated to the D477G mutation; however, neither he nor his 80-year-old asymptomatic father, who also carried the D477G variant, were available for further study.
In a 69-year-old man of Scottish ancestry with a clinical presentation and ophthalmologic imaging consistent with choroideremia, who was negative for mutation in the CHM or other genes, Jauregui et al. (2018) identified heterozygosity for the D477G mutation in the RPE65 gene. The authors amended the patient's diagnosis from choroideremia to adRP, and concluded that RPE65-associated adRP presents with a misleading choroideremia-like phenotype.
Shin et al. (2017) analyzed kinetics of 11-cis retinal regeneration in mice heterozygous for the D477G mutation and suggested that the variant acts as a dominant-negative mutant that delays chromophore regeneration, in a pathogenic mechanism distinct from previously studied recessive RPE65 mutations.
In cotransfected HEK293-F cells, Li et al. (2019) observed no interference by the D477G mutant with wildtype RPE65 isomerase function, and concluded that the mutation does not exert a dominant-negative effect; rather, noting the lower production of 11-cis retinol in cells transfected with the mutant, they suggested that D477G represents a hypomorphic variant. Analysis of mRNA from mutant-transfected cultured cells revealed alternatively spliced transcripts, suggesting that the pathogenesis associated with the variant may involve splicing defects in humans.
Functional Analysis of RPE65 Mutations
Using transfected cultured human primary RPE cells, Li et al. (2014) found that disease-associated mutant RPE65 had lower expression at the protein level than wildtype RPE65. Further analysis showed that the mutant RPE65s were mainly degraded in the proteasome and that PSMD13 promoted degradation. PSMD13 interacted with mutant RPE65s and played an essential role in their degradation. The RPE65 mutants were strongly ubiquitinated in cells, and ubiquitination was important for their degradation. Low-temperature treatment rescued the enzymatic activity of RPE65 with non-active-site mutations, but not with active-site mutation, as PSMD13 had a reduced effect on degradation of non-active-site mutant RPE65s at low temperature. Immunocytochemical analysis showed that mutant RPE65s formed aggregates in cells and that low temperature reduced aggregate formation. Chemical chaperones enhanced the low-temperature rescue effect on mutant RPE65s with non-active-site mutations, as chemical chaperones and low temperature promoted interaction of mutant RPE65s with membranes.
Aguirre et al. (1998) described a 4-bp deletion in the RPE65 gene in a form of retinal dystrophy in dogs of the Swedish Briard breed. The disorder was initially described by Narfstrom et al. (1989) as a stationary disorder analogous to human congenital stationary night blindness (CSNB). The disorder was later described as having a progressive component and was termed hereditary retinal dystrophy (Wrigstad et al., 1994). Aguirre et al. (1998) studied 10 Briard dogs affected with what has been called CSNB in the U.S. The dogs originated from stock in the U.S., Canada, and France. Identification of the same mutation (a homozygous 4-bp deletion resulting in frameshift and a premature stop codon that truncates the protein) suggested a founder effect.
Acland et al. (2001) used recombinant adeno-associated virus (AAV) carrying wildtype Rpe65 to test the efficacy of gene therapy in a canine model of childhood blindness. The treatment consisted of subretinal injection of the recombinant AAV-Rpe65, and the results indicated that the visual function could be restored. Applications to the human were discussed.
Redmond et al. (1998) showed that Rpe65-deficient mice exhibit changes in retinal physiology and biochemistry. Outer segment discs of rod photoreceptors in Rpe65 -/- mice are disorganized compared with those of Rpe65 +/+ and Rpe65 +/- mice. Rod function, as measured by electroretinography, is abolished in Rpe65 -/- mice, although cone function remains. Rpe65 -/- mice lack rhodopsin (180380), but do not lack opsin apoprotein. Furthermore, all-trans-retinyl esters overaccumulate in the RPE of Rpe65 -/- mice, whereas 11-cis-retinyl esters are absent. Thus, disruption of the RPE-based metabolism of all-trans-retinyl esters to 11-cis-retinol appears to underlie the Rpe65 -/- phenotype, although cone pigment regeneration may be dependent on a separate pathway.
Rohrer et al. (2003) studied the amount of regenerable opsin in Rpe65 -/- mice during development and aging. In aged Rpe65 -/- mice, opsin levels decreased because of the loss of photoreceptors. The remaining opsin was structurally intact. The components of the phototransduction cascade and the retinal circuitry remained functional, despite the absence of normal photoreceptor activity.
Grimm et al. (2000) exposed to bright light 2 groups of genetically altered mice that lacked the visual pigment rhodopsin (Rpe65 -/- and Rho -/-). Grimm et al. (2000) showed that photoreceptors lacking rhodopsin in these mice are completely protected against light-induced apoptosis. The transcription factor AP1, a central element in the apoptotic response to light, is not activated in the absence of rhodopsin, indicating that rhodopsin is essential for the generation or transduction of the intracellular death signal induced by light. AP1 complexes in the retina mainly consist of c-Fos and Jun (165160) heterodimers. The level of Fos (164810) mRNA expressed in the retinas of Rpe65 -/- mice was 24% that of wildtype controls. In contrast, both wildtype and Rpe65 -/- mice expressed Jun mRNA at comparable levels.
Van Hooser et al. (2000) introduced 9-cis retinal by oral gavage in Rpe65 -/- mice at 8 to 12 weeks of age, when there were only minimal changes in photoreceptor morphology. Within 48 hours, there was formation of rod photopigment and dramatic improvement in rod physiology as determined by in vivo electroretinograms. These findings demonstrated that mechanism-based pharmacologic intervention has the potential to restore vision in otherwise incurable genetic retinal degenerations.
Whereas previous studies of RPE65 deficiency in both animal models and patients attributed remaining visual function to cones, Seeliger et al. (2001) showed that light-evoked retinal responses in fact originate from rods. They selectively impaired either rod or cone function in Rpe65 -/- mice by generating double-mutant mice with models of pure cone function (Rho -/-) and pure rod function (Cnga3 -/-). The ERGs of Rpe65 -/- and Rpe65-/-Cnga3-/- mice were almost identical, whereas there was no assessable response in Rpe65-/-Rho-/- mice. Seeliger et al. (2001) found also that lack of RPE65 enables rods to mimic cone function by responding under normally cone-isolating lighting conditions.
Van Hooser et al. (2002) found that administration of 9-cis-retinal to Rpe65 -/- mice inhibited the accumulation of all-trans-retinal, improved the attachment contacts between the retinal pigment epithelium and the rod outer segments, led to dephosphorylation of opsin, and prevented the further progression of retinal degeneration, suggesting that ester accumulation in the RPE and the presence of high levels of active opsin in the photoreceptor may be the principal causes of retinal degeneration in the Rpe65 -/- mouse. The light sensitivity of rods from Rpe65 -/- mice was restored in a dose-dependent manner, with the highest dose restoring rod responses with normal sensitivity and kinetics. The reduction in retinal ester accumulation and improvement in rod retinal function continued for more than 6 months after treatment.
Mutations in Rpe65 disrupt synthesis of the opsin chromophore ligand 11-cis-retinal and cause Leber congenital amaurosis-2. To test whether light-independent signaling by unliganded opsin causes the degeneration, Woodruff et al. (2003) used Rpe65-null mice, a model of LCA. Dark-adapted Rpe65 -/- mice behaved as if light-adapted, exhibiting reduced circulating current, accelerated response turnoff, and diminished intracellular calcium. A genetic block of transducin signaling completely rescued degeneration irrespective of an elevated level of retinyl ester. These studies clearly showed that activation of sensory transduction by unliganded opsin, and not the accumulation of retinyl esters, causes light-independent retinal degeneration in LCA. A similar mechanism may also be responsible for degeneration induced by vitamin A deprivation.
The visual pigment rhodopsin (180380) consists of the apoprotein opsin and the retinoid chromophore 11-cis-retinal. Visual signaling is triggered upon photoisomerization of 11-cis-retinal into all-trans-retinal. Reme and Wenzel (2003) reviewed the work of Woodruff et al. (2003), which showed that visual signaling by opsin in the absence of chromophore is a pathogenetic mechanism of visual cell loss.
Znoiko et al. (2005) found that short-wavelength cone opsin (613522) mRNA was markedly decreased in Rpe65 -/- mice at 2 weeks of age, whereas a decrease in middle-wavelength cone opsin (300821) mRNA occurred relatively later in age. Rhodopsin mRNA level did not show any significant change at all ages analyzed. Rpe65 -/- mice showed significant cone loss in both the central and ventral retina between 2 and 3 weeks of age; however, administration of 9- or 11-cis-retinal at 2 weeks of age increased cone density by 2-fold in these areas, partially preventing cone loss. Znoiko et al. (2005) concluded that in Rpe65 -/- mice the expression of cone-specific genes was downregulated and accompanied by early cone degeneration and that absence of 11-cis chromophore may be responsible for the early cone degeneration.
Doyle et al. (2006) found that circadian phase-shifting responses were attenuated in Rpe65 -/- mice beyond that reported for rodless/coneless mice. Furthermore, the number of melanopsin (OPN4; 606665)-positive perikarya and the extent of dendritic arborizations were decreased in Rpe65 -/- mice. Elimination of rods in Rpe65 -/- mice restored circadian photosensitivity. Normal photoentrainment was lost in Rpe65 -/- Opn4 -/- double-knockout mice, which exhibited a diurnal phenotype. Doyle et al. (2006) concluded that RPE65 is not required for function of intrinsically photosensitive retinal ganglion cells, but rods may influence the function of these cells.
Phototransduction in cones is initiated by the bleaching of their visual pigment, which comprises a protein component (cone opsin) and a vitamin A derivative (11-cis retinal). To study the retinoid metabolism of cones, Wenzel et al. (2007) used 2 different mouse models characterized as cone-only models--Nrl -/- (162080) and Rho -/- (180380)--bred to Rpe65-deficient mice. Ablation of Rpe65 in Nrl -/- and Rho -/- mice led to the absence of 11-cis retinal. In the absence of Rpe65, retinal sensitivity in Nrl -/- mice dropped by a factor of a thousand. Wenzel et al. (2007) concluded that RPE65, previously shown to be essential for rod function, is also indispensable for the production of 11-cis retinal for cones and thus for cone function.
Samardzija et al. (2008) generated R91W (180069.0006) knockin mice and found that, in contrast to Rpe65-null mice, low but substantial levels of both RPE65 and 11-cis-retinal were present. Whereas rod function was already impaired in young animals, cone function was less affected. Rhodopsin metabolism and photoreceptor morphology were disturbed, leading to a progressive loss of photoreceptor cells and retinal dysfunction. Samardzija et al. (2008) concluded that the consequences of the R91W mutation were clearly distinguishable from those of an Rpe65-null mutation, as evidenced by the production of 11-cis-retinal and rhodopsin, as well as by less severe morphologic and functional disturbances at an early age.
Samardzija et al. (2009) found that R91W knockin mice demonstrated cone opsin mislocalization and progressive geographic cone atrophy. Remnant visual function was mostly mediated by rods. Ablation of rod opsin corrected the localization of cone opsin and improved cone retinal function. The authors concluded that, under conditions of limited chromophore supply, rods and cones compete for 11-cis-retinal derived from regeneration pathway(s), which are reliant on RPE65. Due to their higher number and the instability of cone opsin, rods are privileged under this condition, while cones suffer chromophore deficiency and degenerate.
Inactivating mutations in the RPE65 and LRAT (604863) genes cause forms of Leber congenital amaurosis (LCA). Maeda et al. (2009) investigated human RPE65-LCA patients and mice with visual cycle abnormalities to determine the impact of chronic chromophore deprivation on cones. Young patients with RPE65 mutations showed foveal cone loss along with shortened inner and outer segments of remaining cones; cone cell loss also was dramatic in young mice lacking Rpe65 or Lrat gene function. To selectively evaluate cone pathophysiology, the authors eliminated the rod contribution to electroretinographic (ERG) responses by generating double-knockout mice lacking Lrat or Rpe65 together with an inactivated Gnat1 gene (139330). Cone ERG responses were absent in Gnat1-null/Lrat-null mice, which also showed progressive degeneration of cones. Cone ERG responses in Gnat1-null/Rpe65-null mice were markedly reduced and declined over weeks. Treatment of these mice with an artificial chromophore prodrug, 9-cis-retinyl acetate, partially protected inferior retinal cones as evidenced by improved ERGs and retinal histochemistry. Gnat1-null mice chronically treated with retinylamine, a selective inhibitor of RPE65, also showed a decline in the number of cones that was ameliorated by 9-cis-retinyl acetate. Maeda et al. (2009) suggested that chronic lack of chromophore may lead to progressive loss of cones in mice and humans, and that therapy for LCA patients could be geared toward early adequate delivery of chromophore to cone photoreceptors.
Shin et al. (2017) generated a D477G (180069.0013) knockin mouse model and did not observe any change in retinal morphology or opsin expression in heterozygous D477G mice compared to wildtype mice. The heterozygous mutants also showed scotopic, maximal, and photopic electroretinography responses comparable to those of wildtype mice. However, kinetics of 11-cis-retinal regeneration after light exposure were significantly slower in the mutants compared to wildtype mice, and the heterozygotes also showed lower A-wave recovery compared to wildtype after photobleaching, consistent with delayed dark adaptation. The authors suggested that D477G acts as a dominant-negative mutant of RPE65 that delays chromophore regeneration.
Choi et al. (2018) generated knockin mice expressing human RPE65 with the D477G mutation. Both heterozygous and homozygous knockin mice showed ubiquitination of mutant RPE65 and decreased expression of RPE65 protein. Moreover, heterozygous and homozygous knockin mice had age-dependent retinal degeneration. Heterozygous and homozygous D477G mutation affected the functional integrity of mouse retina, particularly rod photoreceptors, resulting in reduced scotopic ERG responses. Furthermore, analysis of retinoid composition demonstrated that the D477G mutation reduced the 11-cis-retinal regeneration rate and perturbed the visual cycle in both heterozygous and homozygous knockin mice.
Using CRISPR/Cas9, Li et al. (2019) generated transgenic mice with the c.1430A-G (D477G) mutation. Both heterozygous and homozygous knockin mice showed grossly normal retinal structures and visual functions under the dim light conditions of regular animal husbandry. However, when subject to chronic moderate light exposure, a brief moderate light bleach resulted in degenerative changes in the homozygous knockin mouse retinas, including decreased thickness of the outer nuclear layer, somewhat less tightly packed retinal outer segment, and mild disorganization of the RPE.
In 2 sibs, aged 20 years and 13 years, with Leber congenital amaurosis (LCA2; 204100), Marlhens et al. (1997) found compound heterozygosity for a 1067delA mutation in a stretch of consecutive adenine residues; and a 700T-C transition in a CpG site that resulted in a nonsense mutation, R234X (180069.0002). These mutations were inherited from the mother and father, respectively, who were clinically unaffected. Fundus examination of the patients showed a number of yellowish spots in the outer layers of the retina. In addition, few pigmentary deposits, moderate narrowing of retinal vessels and pallor of the optic disc revealed a lesser-than-expected degree of degeneration. This was similar to some cases of Leber congenital amaurosis in infants, in whom an undetectable electroretinographic response contrasts with an almost normal ophthalmoscopic appearance. Therefore, the severely reduced sight of the 2 sibs was thought to be due partly to dysfunctioning photoreceptors rather than to loss of photoreceptors.
For discussion of the arg234-to-ter (R234X) mutation in the RPE65 gene that was found in compound heterozygous state in sibs with Leber congenital amaurosis-2 (LCA2; 204100) by Marlhens et al. (1997), see 180069.0001.
In a consanguineous Indian family (PMK30) in which 4 individuals had autosomal recessive childhood-onset severe retinal dystrophy, Gu et al. (1997) mapped the disease locus, which they designated RP20 (613794), to chromosome 1p31-p22. Gu et al. (1997) found that all 4 affected individuals were homozygous for a 1141C-A transversion in the RPE65 gene. The 4 parents were heterozygous for the sequence change, as were 3 of the 4 unaffected sibs; the fourth unaffected sib carried only the wildtype sequence. The mutation predicted a nonconservative replacement of the evolutionarily conserved proline-363 by threonine (P363T). The onset of severe visual impairment in this family varied between 3 and 7 years of age. Night blindness was a typical and early symptom in all patients. Most patients became severely visually handicapped between 5 and 12 years of age and could only count fingers at 1 to 3 meters distance or were able to see only hand movements. The 4 patients varied in age from 20 to 32 years. Two had nystagmus, which was consistent with an early onset of severe visual disability. Fundus examination showed attenuated vessels and atrophy of the optic disc. Although bone-spicule formation was not a typical feature, many whitish dots were compatible with extensive RPE defects.
In 3 patients with autosomal recessive retinitis pigmentosa (RP20; 613794), Morimura et al. (1998) identified mutations in the RPE65 gene that are likely to be pathogenic. In 1 of the families, 1 individual with RP was homozygous for a leu341-to-ser mutation, whereas 4 other individuals with RP in other branches of the family were compound heterozygotes for this mutation and a 4-bp insertion affecting glu404.
This variant, formerly titled RETINITIS PIGMENTOSA 20, has been reclassified based on the report of Lek et al. (2016).
In a brother and sister with retinitis pigmentosa (RP20; 613794), Morimura et al. (1998) observed an ala132-to-thr (A132T) mutation in the RPE65 gene in homozygous state.
Lek et al. (2016) found the A132T variant in homozygosity in 4 individuals in the ExAC database and noted that it had a high allele frequency (0.0128) in South Asians, suggesting that it is not pathogenic.
In a patient with isolated RP (RP20; 613794), Morimura et al. (1998) found compound heterozygous mutations in the RPE65 gene: arg91-to-trp and val452-to-gly (180069.0007).
Takahashi et al. (2006) found that injection of human RPE65 containing the R91W mutation into homozygous Rpe65-knockout mice failed to restore isomerohydrolase activity. Analysis in transfected human cells showed that the R91W mutation decreased RPE65 protein level, but not mRNA level, due to decreased protein stability. Wildtype RPE65 was associated with cell membranes, but the R91W mutant localized mainly to cytoplasm. In vitro assays confirmed that the mutation abolished RPE65 enzymatic activity.
For discussion of the val452-to-gly (V452G) mutation in the RPE65 gene that was found in compound heterozygous state in a patient with isolated RP (RP20; 613794) by Morimura et al. (1998), see 180069.0006.
In a 55-year-old Japanese woman, the child of consanguineous parents, who had been diagnosed with retinitis pigmentosa (RP20; 613794) at the age of 40, Kondo et al. (2004) detected a homozygous 1543C-T transition in the RPE65 gene that resulted in an arg515-to-trp (R515W) amino acid substitution. She had observed the development of night blindness in early childhood and had been free from visual disability until 24 years of age. Arg515 is located in a conserved RPE65-specific region. Kondo et al. (2004) noted that this mutation had been found in compound heterozygosity in Leber congenital amaurosis (LCA2; 204100).
In 2 brothers with severe retinal dystrophy in childhood that progressed to near-total vision loss in adulthood (RP20; 613794), Felius et al. (2002) identified compound heterozygosity for a 1156T-C transition in the RPE65 gene, resulting in a tyr368-to-his (Y368H) substitution at a conserved residue, and a +5G-A transition in intron 1 (IVS1+5G-A; 180069.0010). Their asymptomatic mother, who carried the Y368H mutation, had normal visual acuity, light- and dark-adapted visual fields, and electroretinograms (ERGs). Their father, who carried the splice site mutation and also had no vision complaints, was found to have peripheral rod dysfunction and hundreds of tiny hard drusen covering his maculae bilaterally, extending into the rod-rich retina beyond the macular arcades.
In 13 patients with early-onset severe retinal dystrophy (LCA2; 204100) from 9 related Dutch families from a genetically isolated population living on a former island, Yzer et al. (2003) identified homozygosity for the Y368H mutation in the RPE65 gene. A patient from another related family was found to be compound heterozygous for Y368H and the IVS1+5G-A splice site mutation (180069.0010). Among 25 unaffected sibs tested, 17 were heterozygous for the Y368H mutation and 8 did not carry the mutation, and the Y368H mutation was found in 3 (3.1%) of 96 unrelated controls from the same isolated population. Yzer et al. (2003) stated that the Y368H mutation most likely represented a founder mutation inherited from a common ancestor of all 10 Dutch families who was born in the 18th century or earlier. The authors noted that in a study of the same genetically isolated Dutch population, Schappert-Kimmijser et al. (1959) ascertained 13 LCA patients in 8 families; Yzer et al. (2003) predicted that most if not all of those patients carried the Y368H founder mutation. Y368H was not detected in 86 LCA patients from a different white population or in 94 controls from the Netherlands, but analysis of 75 Dutch patients with autosomal recessive or isolated retinitis pigmentosa revealed the presence of the mutation in heterozygosity in 1 Dutch patient with RP and early-onset vision loss.
Takahashi et al. (2006) found that injection of human RPE65 containing the Y368H mutation into homozygous Rpe65-knockout mice failed to restore isomerohydrolase activity. Analysis in transfected human cells showed that the Y368H mutation decreased RPE65 protein level, but not mRNA level, due to decreased protein stability. Wildtype RPE65 was associated with cell membranes, but the Y368H mutant localized mainly to cytoplasm. In vitro assays confirmed that the mutation abolished RPE65 enzymatic activity.
For discussion of the splice site mutation (IVS1+5G-A) in the RPE65 gene that was found in compound heterozygous state in 2 brothers with retinitis pigmentosa-20 (RP20; 613794) by Felius et al. (2002), see 180069.0009.
Felius et al. (2002) stated that the IVS1+5G-A splice site mutation was the most common of the known RPE65 mutations and that it occurred on at least 2 genetic backgrounds.
For discussion of a patient with Leber congenital amaurosis-2 (LCA2; 204100) reported by Yzer et al. (2003) who was compound heterozygous for IVS1+5G-A and Y368H in the RPE65 gene, see 180069.0009.
In a 35-year-old woman with Leber congenital amaurosis (LCA2; 204100), Al-Khayer et al. (2004) identified compound heterozygosity for 2 mutations in the RPE65 gene: a 961A-T transversion, resulting in a lys303-to-ter (K303X) substitution, and a 1346A-G transition, resulting in a tyr431-to-cys (Y431C; 180069.0012) substitution.
For discussion of the tyr431-to-cys (Y431C) mutation that was found in compound heterozygous state in a woman with Leber congenital amaurosis (LCA2; 204100) by Al-Khayer et al. (2004), see 180069.0011.
In 20 affected members of a large 4-generation Irish family (TCD-G) segregating autosomal dominant retinitis pigmentosa with choroidal involvement that mapped to chromosome 1p31 (RP87; 618697), Bowne et al. (2011) identified heterozygosity for a c.1430G-A transition (c.1430G-A, NM_000329) in exon 13 of the RPE65 gene, resulting in an asp477-to-gly (D477G) substitution at a highly conserved residue. The mutation, which was not found in 684 Irish control chromosomes, was also detected in 4 unaffected family members, indicating incomplete penetrance. Screening for the D477G mutation in 12 Irish patients with a range of inherited retinal degenerations identified a man (family TCD-H) diagnosed with choroideremia (see 303100) but negative for mutation in the CHM gene (300390), who carried the D477G variant; the variant was also found in his 2 affected daughters. The mutation was shown to have occurred on the same haplotype as in family TCD-G, and the authors stated that the clinical phenotype in TCD-H was consistent with that of family TCD-G. SDS-PAGE analysis demonstrated that the mutant protein migrated marginally faster than wildtype RPE65, whereas Western blot analysis showed that expression of both wildtype and mutant RPE65 remained unchanged in membrane fractions.
In 5 affected individuals from 2 families of Irish ancestry with autosomal dominant retinal dystrophy phenotypes, Hull et al. (2016) identified the RPE65 D477G mutation. The authors noted that 4 of the 5 affected individuals exhibited severe disease resembling choroideremia, with much more extensive RPE and choroidal degeneration than retinal degeneration, although ERGs showed a rod-cone pattern of photoreceptor degeneration. In contrast, the fifth patient (patient 2.3) presented with adult-onset vitelliform macular dystrophy (see 153840), which the authors suggested might be unrelated to the D477G mutation; however, neither he nor his 80-year-old asymptomatic father, who also carried the D477G variant, were available for further study.
In a 69-year-old man of Scottish ancestry whose clinical presentation and ophthalmologic imaging were consistent with choroideremia, but who was negative for mutation in CHM or other genes, Jauregui et al. (2018) identified heterozygosity for the D477G mutation in the RPE65 gene. The authors amended the patient's diagnosis from choroideremia to adRP, and they concluded that RPE65-associated adRP presents with a misleading choroideremia-like phenotype. Family members, including a similarly affected sister, were unavailable for segregation analysis. The authors noted that the patient stated that his ancestors may have migrated from Scotland to Ireland.
In a D477G knockin mouse model, Shin et al. (2017) observed that kinetics of 11-cis-retinal regeneration after light exposure were significantly slower in heterozygous mutants compared to wildtype mice. Heterozygotes also showed lower A-wave recovery compared to wildtype after photobleaching, consistent with delayed dark adaptation. The authors suggested that D477G acts as a dominant-negative mutant of RPE65 that delays chromophore regeneration.
Using transfected cell lines, Choi et al. (2018) demonstrated that the human RPE65 D477G mutation did not affect expression, subcellular localization, or isomerization activity of RPE65 in vitro. Structural analysis of an RPE65 chimera showed that the D477G mutation did not perturb protein folding or tertiary structure, but instead triggered a gain of protein-protein interaction potential by allowing the D477G loop to form contacts with diverse molecular surfaces.
In HEK293-F cells transfected with the RPE65 D477G mutant, Li et al. (2019) observed production of about half of the 11-cis retinol produced by cells transfected with wildtype RPE65, with comparable protein expression levels. In addition, when the mutant was cotransfected with wildtype at a 1:1 ratio, there was no interference by the mutant with wildtype isomerase function. The authors concluded that D477G does not have a dominant-negative effect, but rather behaves like a hypomorphic variant. Analysis of mRNA transcripts from homozygous D477G knockin mice revealed multiple products of ectopic splicing events, all of which caused a frameshift resulting in a premature termination codon. The authors stated that instead of working as a strong cryptic splicing site, the mutation appears to impair recognition of the correct acceptor splice site at the 3-prime end of intron 12, thus forcing the spliceosome to search for alternative acceptor sites in a rather undefined fashion. Similar splicing defects were confirmed for the human RPE65 c.1430G mutant in cultured cells.
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