Alternative titles; symbols
ORPHA: 791; DO: 0110372;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 3q22.1 | Retinitis pigmentosa 4, autosomal dominant or recessive | 613731 | Autosomal dominant; Autosomal recessive | 3 | RHO | 180380 |
A number sign (#) is used with this entry because retinitis pigmentosa-4 (RP4) is caused by heterozygous, and rarely by homozygous, mutation in the RHO gene (180380) on chromosome 3q22.
For a phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.
Bradley et al. (1989, 1989) reported a large 5-generation Irish family segregating autosomal dominant early-onset retinitis pigmentosa. Affected status was determined by extinguished responses on electroretinogram (ERG) and/or symptoms characteristic of RP, including nyctalopia and peripheral visual field loss. In addition, all affected individuals exhibited funduscopic disturbances typical of RP: disc pallor, attenuation of retinal vessels, and classic bone-spicule pigmentary deposits in the retinal periphery. All of those affected reported difficulty with night vision before the age of 10 years, and extinguished ERG patterns coupled with funduscopic disturbances were obtained in 4 children aged 6 to 10 years.
Of the 12 families with RP in which mutations in the RHO gene were identified by Inglehearn et al. (1992), 4 had the D type, 3 had the sectoral type, and the remainder were of uncertain classification. All families excluded from chromosome 3q by linkage had been classified R type. The sectoral type of RP affects only 1 or 2 quadrants of the retina, with the remaining retina left intact. The disease is nonprogressive or progresses very slowly. The D type causes 'diffuse' and severe loss of rod function with retention of cone function until much later in the disease process. ERG and psychophysical testing show that rod function is abnormal over the entire fundus. The R type causes 'regional' or patchy and equal loss of rod and cone function.
Van Schil et al. (2016) reported a Turkish brother and sister with an 'unusual retinitis pigmentosa phenotype' and mutation in the RHO and SAMD7 (620493) genes. The 49-year-old brother and his 44-year-old sister had onset of night blindness and visual field constriction in the second decade of life. Examination showed reduced visual acuity and concentric visual field constriction, and the brother also exhibited a color vision defect in the blue-yellow axis. Funduscopy showed retinal atrophy with vascular attenuation and a relatively preserved macula. In addition to the classic spicular intraretinal pigmentation, both patients showed nummular intraretinal pigment deposits, and there were several well-delineated areas of punched-out retinal atrophy. Examination of 2 of their sibs and their mother was unremarkable, but a 47-year-old brother who reported night blindness showed slightly reduced visual acuity; funduscopy revealed minor subclinical manifestations, including multiple zones of peripheral intraretinal pigmentation with either a spicular or nummular appearance, and multiple white dots.
In a large Irish kindred segregating retinitis pigmentosa in which the disorder was previously excluded from the short arm of chromosome 1 (Bradley et al. (1989, 1989)), McWilliam et al. (1989) localized the disorder to 3q by demonstration of tight linkage to D3S47; maximum lod score = 14.4 at theta = 0.00. The marker they used was placed approximately 36 cM distal to D3S1, which had been localized to 3q12 by Donis-Keller et al. (1987). Because of the coincidence of mapping of the RP gene in the Irish kindred and the rhodopsin gene to 3q, the mutation presumably resided in the rhodopsin gene, thus starting a search for mutations.
In a large Australian kindred with what was referred to as type II autosomal dominant RP, Olsson et al. (1990) found linkage to marker D3S47 located on 3q; maximum lod = 4.78 at theta = 0.08. The results in the 2 families, Irish (McWilliam et al., 1989) and Australian, gave confidence limits that were overlapping. However, Olsson et al. (1990) raised the possibility of the existence of 2 separate RP loci on 3q and pointed out that, in addition to rhodopsin, there are 2 other candidate genes, those for retinol binding proteins 1 and 2 (180260, 180280), located on 3q. By statistical analysis, Kumar-Singh et al. (1993) concluded that there is only one autosomal dominant RP locus on 3q. They performed an admixture test on 10 D3S47-linked retinitis pigmentosa pedigrees and also on all families with known rhodopsin mutations.
In patients with autosomal dominant retinitis pigmentosa mapping to 3q, Dryja et al. (1990) identified a heterozygous pro23-to-his mutation (P23H; 180380.0001) in the RHO gene. The proline residue at position 23 in the NH2 portion of the rhodopsin gene is highly conserved. Dryja et al. (1990) reported 3 additional missense mutations (180380.0002-180380.0004) in the RHO gene in patients with RP4. They found that these 4 mutations accounted for 27 of 150 unrelated patients with ADRP (18%).
In the original family (TCDM1) with autosomal dominant retinitis pigmentosa linked to 3q (McWilliam et al., 1989), Farrar et al. (1992) identified an arg207-to-met mutation (180380.0030) in the RHO gene.
On the basis of a complete screen for mutations in the RHO gene in patients with autosomal dominant retinitis pigmentosa, Inglehearn et al. (1992) concluded that approximately 30% of such families have 'rhodopsin rp,' whereas the remainder probably have a defect elsewhere in the genome. Specifically they found 9 different RHO mutations in a total of 12 out of 39 families screened.
In a 5-generation Chinese Bai family segregating autosomal dominant RP mapping to chromosome 3q, Guo et al. (2010) identified heterozygosity for the P347L mutation in the RHO gene (180380.0002). The authors stated that, although mutations in RHO account for approximately 7.7% of autosomal dominant RP in the Chinese Han population, this was the first RHO mutation reported in RP patients of the Chinese Bai nationality.
In affected members of 2 Indonesian families segregating autosomal recessive RP4, Kartasasmita et al. (2011) identified a homozygous nonsense mutation in the RHO gene (180380.0045). Haplotype analysis suggested that this is a founder mutation.
In a Turkish brother and sister with an unusual RP phenotype, Van Schil et al. (2016) identified homozygosity for a previously reported missense mutation in the RHO gene (E150K; 180380.0033) as well as homozygosity for 4 noncoding variants in the SAMD7 gene (620493). Their unaffected mother and 2 unaffected sisters were heterozygous for the RHO and SAMD7 variants, as was a brother with minor subclinical manifestations. The authors suggested that the unusual nummular intraretinal pigment deposits observed in the affected sibs might be attributed to the SAMD7 variants, and postulated the presence of other modifying factors to account for the heterozygous brother's manifestations.
Jacobson et al. (1991) studied rod and cone function in 20 patients from 6 families with autosomal dominant RP due to 5 different point mutations in the rhodopsin gene. In addition to traditional ocular examination methods and electroretinography, they performed dark- and light-adapted perimetry, dark adaptometry, and imaging fundus reflectometry. Jacobson et al. (1991) observed discernible differences in the pattern of retinal dysfunction between families with different mutations (see T58R, 180380.0004; T17M, 180380.0006; and Q344X, 180380.0015) and noted that 3 families with mutations at the same amino acid position, arg135 (see R135W, 180380.0012, and R135L, 180380.0011), showed a similar functional phenotype involving early, severe retinal dysfunction with no intrafamilial variability.
Andreasson et al. (1992) reported a 6-generation Swedish family segregating autosomal dominant retinitis pigmentosa in whom they identified an R135L mutation (180380.0011). They noted that affected members of this family had a history of night blindness from early childhood and visual field losses were always noted before age 20. Andreasson et al. (1992) concluded that the R135L mutation may cause a more rapidly progressive form of RP than other mutations.
Pannarale et al. (1996) studied a large Sicilian pedigree with autosomal dominant retinitis pigmentosa due to the R135W mutation (180380.0012) in the rhodopsin molecule. The rate of progression of disease was unusually high, with an average 50% loss per year of baseline ERG amplitude and visual field area. Later in the course of the disease, macular function was also severely compromised, leaving only residual central vision by the fourth decade of life. Pannarale et al. (1996) concluded that the phenotype associated with mutations in codon 135 of the rhodopsin molecule appears to have an unusually high progression rate and to yield an extremely poor prognosis.
Ponjavic et al. (1997) examined a 4-generation Swedish RP family with the R135W mutation, in whom they documented a severe form of RP similar to the phenotype observed by Andreasson et al. (1992) in a family with the R135L mutation. Ponjavic et al. (1997) noted that both mutations cause the substitution of hydrophobic amino acids at codon 135, and that point mutations in this specific region of the rhodopsin molecule seem to cause an aggressive form of retinitis pigmentosa.
Oh et al. (2000) reported the clinical characteristics of a family with autosomal dominant retinitis pigmentosa caused by a pro23-to-ala mutation (P23A; 180380.0043) in the rhodopsin gene, and compared this phenotype with that associated with the more common pro23-to-his mutation (P23H; 180380.0001). The rare P23A mutation caused a mild RP in presentation and course, with greater preservation of ERG amplitudes than that resulting from the more prevalent P23H mutation.
Sandberg et al. (2007) measured the rates of visual acuity, visual field, and electroretinogram (ERG) loss in 2 large cohorts, one of patients with XLRP (RP3; 300029) due to mutations in the RPGR gene (312610) and the other of patients with autosomal dominant RP due to mutations in the RHO gene. Patients with RPGR mutations lost Snellen visual acuity at more than twice the mean rate of patients with RHO mutations. The median age of legal blindness was 32 years younger in patients with RPGR mutation than in patients with RHO mutations. Legal blindness was due primarily to loss of visual acuity in RPGR patients and to loss of visual field in RHO patients.
Using longitudinal data, Sakami et al. (2011) found that the earliest expression of retinal disease in ADRP patients with the P23H opsin mutation involved abnormal thinning of the outer nuclear layer and shortening of the rod outer segment. These changes were followed by shortening of the cone outer segment. With more extensive disease, there was further abnormality of inner and outer segments, followed by loss of all remaining photoreceptors.
In a randomized, controlled, double-masked trial, Berson et al. (1993) concluded that oral vitamin A supplementation slowed, on average, the rate of retinal degeneration in adult patients with the common forms of retinitis pigmentosa. The conclusion was based on measuring the rate of electroretinogram (ERG) amplitude decline. Li et al. (1998) monitored the course of photoreceptor degeneration in 2 murine models of retinitis pigmentosa fed a diet containing either a normal or a higher amount of vitamin A. As the murine model of RP, they chose transgenic mice with the thr17-to-met (T17M) mutation (180380.0006) and mice with the pro347-to-ser (P347S; 180380.0003) mutation of the rhodopsin gene. The P347S mutation was chosen to be representative of class I mutant opsins, which are indistinguishable from wildtype opsin in all in vitro assays, including formation of photo pigment and efficient transport to the plasma membrane. The T17M mutation was selected as an example of class II mutant opsins, which are defective in thermal stability/folding, lack full regenerability with the chromophore 11-cis-retinal, and fail to reach the plasma membrane. In vivo, the P347S mutation appeared to cause aberrant transport of rhodopsin, possibly by disrupting a signal sequence that normally directs the vectorial transport of rhodopsin to the outer segments. Li et al. (1998) hypothesized that class II rhodopsin mutants are more likely to respond to vitamin A supplementation than are class I mutants. One putative mechanism through which vitamin A supplementation may slow photoreceptor degeneration is by increasing the availability of the chromophore, 11-cis-retinal. Chromophore binding increases the thermal stability of wildtype opsin and might stabilize the class II mutant rhodopsin. Li et al. (1998) found that a high vitamin A diet significantly reduced the rate of decline of a-wave and b-wave amplitudes in mice carrying a T17M rhodopsin mutation (class II) but had no significant effect on the decline of ERG amplitude in P347S (class I) mice. Correspondingly, histologic evaluation showed that the treatment was associated with significantly longer photoreceptor inner and outer segments and a thicker outer nuclear layer in the T17M mice but had no effect on photoreceptor morphology in the P347S mice. In a separate series of experiments, Li et al. (1998) found that the instability defect of the T17M mutant opsin expressed in vitro was partially alleviated by inclusion of 11-cis-retinal in the culture media. These results suggested that vitamin A supplementation can confer therapeutic benefit in the case of class II rhodopsin mutations by stabilizing mutant opsins through increased availability of the chromophore.
O'Reilly et al. (2007) noted that mutational heterogeneity represents a significant barrier to development of therapies for many dominantly inherited diseases. For example, more than 100 mutations in the rhodopsin gene have been identified in patients with retinitis pigmentosa. The development of therapies for dominant disorders that correct the primary genetic lesion and overcome mutational heterogeneity is challenging. Hence, therapeutics comprising 2 elements--gene suppression in conjunction with gene replacement--had been investigated. Suppression is targeted to a site independent of the mutation; therefore, both mutant and wildtype alleles are suppressed. In parallel with suppression, a codon-modified replacement gene refractory to suppression is provided. O'Reilly et al. (2007) undertook both in vitro and in vivo validation of suppression and replacement of RHO-associated retinitis pigmentosa. RNA interference (RNAi) was used to achieve approximately 90% in vivo suppression of RHO in photoreceptors, with use of adeno-associated virus (AAV) for delivery. Demonstration that codon-modified RHO genes express functional wildtype protein was explored transgenically, together with in vivo expression of AAV-delivered RHO-replacement genes in the presence of targeting RNAi molecules. Observation of potential therapeutic benefit from AAV-delivered suppression and replacement therapies was obtained in mice with the pro23-to-his mutation (180380.0001). Results provided the first in vivo indication that suppression and replacement can provide a therapeutic solution for dominantly inherited disorders such as RHO-associated RP and can be employed to circumvent mutational heterogeneity.
Hernan et al. (2011) investigated the cellular expression of cis-acting splicing mutations in the RHO gene that lead to autosomal dominant or recessive RP and the role of nonsense-mediated mRNA decay (NMD) in its pathogenic mechanisms, hoping to design a potential therapeutic RNAi-based suppression strategy for cis-acting adRP splicing mutants. Two RHO cis-acting splicing mutations causing adRP (531-2A-G and 937-1G-T) induced cryptic splicing. In contrast, a 936+1G-T mutation, causing arRP, resulted in exon skipping. Although the 531-2A-G and 745G-T RHO sequences predicted a premature termination codon (PTC) that should be a target for NMD, these mutant proteins were detected in transfected cells. The siRNAs designed to interfere with adRP mutants silence the corresponding mRNA with varying efficiency. Thus, different levels of mutant protein might be necessary to trigger the RP phenotype. Hernan et al. (2011) concluded that their findings demonstrate the potential use of siRNA to interfere with cis-acting splicing RHO transcripts, but noted that limitations in the mutation sequence and incomplete mutant transcript elimination should be considered in a therapeutic approach for adRP.
To investigate the mechanism by which the presence of both mutated rhodopsin and normal rhodopsin leads to the slow degeneration of the photoreceptor cells, Naash et al. (1993) established a transgenic mouse line that carried a mutated mouse opsin gene in addition to the endogenous opsin gene. The alterations consisted of 3 amino acid substitutions near the N terminus of which 1 was the P23H mutation. During early postnatal development, mice heterozygous for the mutated opsin gene appeared to develop normal photoreceptors, but their light-sensitive outer segments never reached normal length. With advancing age, both rod and cone photoreceptors were reduced progressively in number. The slow degeneration of the transgenic retina was associated with a gradual decrease of light-evoked electroretinogram responses.
Lem et al. (1999) stated that mutations in the RHO gene account for approximately 15% of all inherited human retinal degenerations. Investigations into the pathophysiologic and molecular events underlying these disease processes have included studies of transgenic mice expressing opsin genes containing defined mutations. A caveat of this approach is that even the overexpression of normal opsin levels leads to photoreceptor cell degeneration (Olsson et al., 1992). To overcome this problem, Lem et al. (1999) reduced or eliminated endogenous rhodopsin by targeted gene disruption. Retinas in mice lacking both opsin alleles initially developed normally, except that rod outer segments failed to form. Within months of birth, photoreceptor cells degenerated completely. Retinas from mice with a single copy of the opsin gene developed normally, and rods elaborated outer segments of normal size but with half the normal complement of rhodopsin. Photoreceptor cells in these retinas also degenerated but did so over a much slower time course. Physiologic and biochemical experiments showed that rods from mice with a single opsin gene were approximately 50% less sensitive to light, had accelerated flash-response kinetics, and contained approximately 50% more phosducin (171490) than wildtype controls.
To understand better the functional and structural role of rhodopsin in normal retina and the pathogenesis of retinal disease, Humphries et al. (1997) generated mice carrying a targeted disruption of the Rho gene. Rho -/- mice did not elaborate rod outer segments and lost their photoreceptors over 3 months. There was no rod ERG response in 8-week-old animals. Heterozygous animals retained most of their photoreceptors, although the inner and outer segments of these cells displayed some structural disorganization, the outer segments becoming shorter in older mice. Humphries et al. (1997) commented that these animals should provide a useful genetic background on which to express other mutant opsin transgenes, as well as a model to assess therapeutic potential of reintroducing functional rhodopsin genes into degenerating retinal tissues.
Kijas et al. (2002) identified English Mastiff dogs with a naturally occurring autosomal dominant retinal degeneration and determined the cause to be a thr4-to-arg mutation in the Rho gene. Dogs with this mutant allele manifested a retinal phenotype that closely mimicked that in humans with RHO mutations. The phenotypic features shared by dog and man included a dramatically slowed time course of recovery of rod photoreceptor function after light exposure and a distinctive topographic pattern of the retinal degeneration. The Rho mutant dog should be useful in preclinical trials of therapies.
Organisciak et al. (2003) found that light-induced retinal damage in transgenic rats depended on the time of day of exposure to light, prior light-or-dark-rearing environment, and the relative level of rhodopsin-transgene expression. Retinal light damage led to apoptotic photoreceptor cell loss and appeared to result from oxidative stress. The authors concluded that reduced environmental lighting and/or antioxidant treatment may delay retinal degenerations arising from rhodopsin mutations.
Jacobson and McInnes (2002) commented on the demonstration of the different pathways, a bright-light pathway and a low-light-dependent pathway. Although both pathways are initiated by excessive activation of the photopigment rhodopsin, they differ in that only the bright-light pathway is AP-1-dependent and only the low-light pathway is dependent on phototransduction.
White et al. (2007) found that expression of a human T17M mutant rhodopsin transgene in mice was associated with photoreceptor apoptosis in response to moderate exposure to light. This phenotype was not observed in nontransgenic littermates or in mice expressing a human P28H mutant rhodopsin transgene. White et al. (2007) noted that the T17M mutation abolishes glycosylation at the asn15 site of rhodopsin. They suggested that elimination of glycosylation at this site is associated with increased sensitivity to light-induced damage.
Congenital night blindness affects retinal rod photoreceptor cells and is expressed as an inability to see under dim light conditions. The disease appears to be caused by inappropriate stimulation, and consequent desensitization, of rod cells, and 2 models have been proposed for the source of the stimulatory signal. Model I suggests that the signal comes from constitutively active mutant apoprotein, or opsin, generated by thermal dissociation of 11-cis-retinal. Model II suggests that desensitization is caused by metarhodopsin II, an intermediate formed from increased thermal isomerization of the 11-cis-retinal chromophore in the mutant rhodopsins. Using a transgenic Xenopus model with disease-causing mutations, Jin et al. (2003) showed that incubation with exogenously added 11-cis-retinal resulted in recovery of wildtype sensitivity, findings that argue against the thermal isomerization theory of model II. The authors concluded that constitutively active mutant opsin cause the desensitization of the congenital night blindness photoreceptor cells, consistent with model I.
Galy et al. (2005) reported that P37H-transgenic flies, which correspond to the human P23H mutation (180380.0001), exhibited dominant photoreceptor degeneration, mimicking human age-, light-dependent and progressive ADRP. Most of mutant protein accumulated in endoplasmic reticulum, and expression of mislocalized mutant Rho led to cytotoxicity via activation of 2 stress-specific MAPKs, p38 (MAPK14; 600289) and JNK (MAPK8; 601158), which are known to control stress-induced apoptosis. In P37H-mutant flies, visual loss and degeneration were accompanied by apoptotic features and were prevented by expression of the baculovirus p35 apoptosis inhibitor.
Fernandez-Sanchez et al. (2011) evaluated the preventive effect of tauroursodeoxycholic acid (TUDCA) on photoreceptor degeneration, synaptic connectivity, and functional activity of the retina in the transgenic P23H rat, an animal model of autosomal dominant retinitis pigmentosa. TUDCA treatment was capable of preserving cone and rod structure and function, together with their contacts with their postsynaptic neurons. The amplitude of the electroretinogram a- and b-waves was significantly higher in TUDCA-treated animals under both scotopic and photopic conditions than in controls. TUDCA-treated P23H rats showed 3-fold more photoreceptors than control animals and photoreceptor morphology was preserved. Presynaptic and postsynaptic elements, as well as the synaptic contacts between photoreceptors and bipolar or horizontal cells, were preserved in TUDCA-treated P23H rats. Fernandez-Sanchez et al. (2011) concluded that the neuroprotective effects of TUDCA made the compound potentially useful for delaying retinal degeneration in RP.
Patrizi et al. (2021) performed allele-specific editing in a mouse model of adRP4. The mouse model carries 2 copies of the wildtype RHO gene and several copies of the P347S (180380.0003) mutant RHO gene, and expresses the resultant opsin protein with wildtype and P347S alleles in a 1:1 ratio. Patrizi et al. (2021) used CRISPR/Cas9 with 2 different gRNAs designed to target the P347S mutation while preserving the wildtype allele. The CRISPR/Cas9 components were packaged into AAV 2/8 vectors and injected subretinally into mutant 1-week-old mice. Analysis of mRNA from retinas of the treated mice showed reduced expression of the mutant RHO transcript. Electroretinogram studies in the treated mutant mice 1 month after injection showed significant improvement in b-wave amplitudes. Furthermore, mice treated with one of the 2 gRNAs showed improved pupillary constriction to light stimuli. Patrizi et al. (2021) concluded that the findings provided evidence for efficacy of CRISPR/Cas9-mediated allele-specific editing in adRP4.
A second locus for autosomal dominant RP, independent of the rhodopsin locus and called RP5, had been postulated by Olsson et al. (1990), McInnes and Bascom (1992), and Inglehearn et al. (1992). McInnes and Bascom (1992) commented that ironically no mutation in the rhodopsin gene had been found in the large Irish kindred studied by McWilliam et al. (1989) in which linkage of RP to 3q first stimulated search for rhodopsin mutations. They argued that although a mutation in a regulatory element had not been entirely excluded, the failure of 2 null alleles to result in abnormalities in obligate heterozygotes (Rosenfeld et al. (1992, 1992)) made it unlikely that a carrier of a regulatory domain mutation that reduced even to nothing the synthesis of a normal rhodopsin molecule would show photoreceptor degeneration in the heterozygous state. However, Inglehearn et al. (1993) later reported that mutations in the rhodopsin gene had been found in all 3 families with the presumably RHO-unlinked chromosome 3q form of RP: the Irish family of McWilliam et al. (1989) was found to have a met207-to-arg mutation (180380.0030); the family reported by Lester et al. (1990) was found to have a tyr178-to-cys mutation (180380.0013); and the family reported by Olsson et al. (1990) was found to have a thr58-to-arg mutation (180380.0004).
Andreasson, S., Ehinger, B., Abrahamson, M., Fex, G. A six-generation family with autosomal dominant retinitis pigmentosa and a rhodopsin gene mutation (arginine-135-leucine). Ophthalmic Paediat. Genet. 13: 145-153, 1992. [PubMed: 1484692] [Full Text: https://doi.org/10.3109/13816819209046483]
Berson, E. L., Rosner, B., Sandberg, M. A., Hayes, K. C., Nicholson, B. W., Weigel-DiFranco, C., Willett, W. A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Arch. Ophthal. 111: 761-772, 1993. [PubMed: 8512476] [Full Text: https://doi.org/10.1001/archopht.1993.01090060049022]
Bradley, D. G., Farrar, G. J., Sharp, E., Kenna, P., Humphries, M. M., McWilliam, P., Humphries, P. Exclusion mapping of the autosomal dominant retinitis pigmentosa (RP1) locus from the short arm of chromosome 1. (Abstract) Cytogenet. Cell Genet. 51: 968, 1989.
Bradley, D. G., Farrar, G. J., Sharp, E. M., Kenna, P., Humphries, M. M., McConnell, D. J., Daiger, S. P., McWilliam, P., Humphries, P. Autosomal dominant retinitis pigmentosa: exclusion of the gene from the short arm of chromosome 1 including the region surrounding the Rhesus locus. Am. J. Hum. Genet. 44: 570-576, 1989. [PubMed: 2564733]
Donis-Keller, H., Green, P., Helms, C., Cartinhour, S., Weiffenbach, B., Stephens, K., Keith, T. P., Bowden, D. W., Smith, D. R., Lander, E. S., Botstein, D., Akots, G., and 21 others. A genetic linkage map of the human genome. Cell 51: 319-337, 1987. [PubMed: 3664638] [Full Text: https://doi.org/10.1016/0092-8674(87)90158-9]
Dryja, T. P., McGee, T. L., Hahn, L. B., Cowley, G. S., Olsson, J. E., Reichel, E., Sandberg, M. A., Berson, E. L. Mutations within the rhodopsin gene in patients with autosomal dominant retinitis pigmentosa. New Eng. J. Med. 323: 1302-1307, 1990. [PubMed: 2215617] [Full Text: https://doi.org/10.1056/NEJM199011083231903]
Dryja, T. P., McGee, T. L., Reichel, E., Hahn, L. B., Cowley, G. S., Yandell, D. W., Sandberg, M. A., Berson, E. L. A point mutation of the rhodopsin gene in one form of retinitis pigmentosa. Nature 343: 364-366, 1990. [PubMed: 2137202] [Full Text: https://doi.org/10.1038/343364a0]
Farrar, G. J., Findlay, J. B. C., Kumar-Singh, R., Kenna, P., Humphries, M. M., Sharpe, E., Humphries, P. Autosomal dominant retinitis pigmentosa: a novel mutation in the rhodopsin gene in the original 3q linked family. Hum. Molec. Genet. 1: 769-771, 1992. [PubMed: 1302614] [Full Text: https://doi.org/10.1093/hmg/1.9.769]
Fernandez-Sanchez, L., Lax, P., Pinilla, I., Martin-Nieto, J., Cuenca, N. Tauroursodeoxycholic acid prevents retinal degeneration in transgenic P23H rats. Invest. Ophthal. Vis. Sci. 52: 4998-5008, 2011. Note: Erratum: Invest. Ophthal. Vis. Sci. 57: 3820 only, 2016. [PubMed: 21508111] [Full Text: https://doi.org/10.1167/iovs.11-7496]
Galy, A., Roux, M. J., Sahel, J. A., Leveillard, T., Giangrande, A. Rhodopsin maturation defects induce photoreceptor death by apoptosis: a fly model for rhodopsin(pro23his) human retinitis pigmentosa. Hum. Molec. Genet. 14: 2547-2557, 2005. [PubMed: 16049034] [Full Text: https://doi.org/10.1093/hmg/ddi258]
Guo, H., Qin, Y., Meng, Q., Zhang, H., Jin, H., Chen, Y. Linkage analysis and mutation screening of the rhodopsin gene in a Chinese Bai family with autosomal dominant retinitis pigmentosa. J. Hum. Genet. 55: 571-576, 2010. [PubMed: 20555336] [Full Text: https://doi.org/10.1038/jhg.2010.68]
Hernan, I., Gamundi, M. J., Planas, E., Borras, E., Maseras, M., Carballo, M. Cellular expression and siRNA-mediated interference of rhodopsin cis-acting splicing mutants associated with autosomal dominant retinitis pigmentosa. Invest. Ophthal. Vis. Sci. 52: 3723-3729, 2011. [PubMed: 21357407] [Full Text: https://doi.org/10.1167/iovs.10-6933]
Humphries, M. M., Rancourt, D., Farrar, G. J., Kenna, P., Hazel, M., Bush, R. A., Sieving, P. A., Sheils, D. M., McNally, N., Creighton, P., Erven, A., Boros, A., Gulya, K., Capecchi, M. R., Humphries, P. Retinopathy induced in mice by targeted disruption of the rhodopsin gene. Nature Genet. 15: 216-219, 1997. [PubMed: 9020854] [Full Text: https://doi.org/10.1038/ng0297-216]
Inglehearn, C. F., Keen, T. J., Bashir, R., Jay, M., Fitzke, F., Bird, A. C., Crombie, A., Bhattacharya, S. A completed screen for mutations of the rhodopsin gene in a panel of patients with autosomal dominant retinitis pigmentosa. Hum. Molec. Genet. 1: 41-45, 1992. [PubMed: 1301135] [Full Text: https://doi.org/10.1093/hmg/1.1.41]
Inglehearn, C., Farrar, J., Denton, M., Gal, A., Humphries, P., Bhattacharya, S. Evidence against a second autosomal dominant retinitis pigmentosa locus close to rhodopsin on chromosome 3q. (Letter) Am. J. Hum. Genet. 53: 536-537, 1993. [PubMed: 8328469]
Jacobson, S. G., Kemp, C. M., Sung, C.-H., Nathans, J. Retinal function and rhodopsin levels in autosomal dominant retinitis pigmentosa with rhodopsin mutations. Am. J. Ophthal. 112: 256-271, 1991. [PubMed: 1882937] [Full Text: https://doi.org/10.1016/s0002-9394(14)76726-1]
Jacobson, S. G., McInnes, R. R. Blinded by the light. Nature Genet. 32: 215-216, 2002. [PubMed: 12355075] [Full Text: https://doi.org/10.1038/ng1002-215]
Jin, S., Cornwall, M. C., Oprian, D. D. Opsin activation as a cause of congenital night blindness. Nature Neurosci. 6: 731-735, 2003. [PubMed: 12778053] [Full Text: https://doi.org/10.1038/nn1070]
Kartasasmita, A., Fujiki, K., Iskandar, E., Sovani, I., Fujimaki, T., Murakami, A. A novel nonsense mutation in rhodopsin gene in two Indonesian families with autosomal recessive retinitis pigmentosa. Ophthalmic Genet. 32: 57-63, 2011. [PubMed: 21174529] [Full Text: https://doi.org/10.3109/13816810.2010.535892]
Kijas, J. W., Cideciyan, A. V., Aleman, T. S., Pianta, M. J., Pearce-Kelling, S. E., Miller, B. J., Jacobson, S. G., Aguirre, G. D., Acland, G. M. Naturally occurring rhodopsin mutation in the dog causes retinal dysfunction and degeneration mimicking human dominant retinitis pigmentosa. Proc. Nat. Acad. Sci. 99: 6328-6333, 2002. [PubMed: 11972042] [Full Text: https://doi.org/10.1073/pnas.082714499]
Kumar-Singh, R., Wang, H., Humphries, P., Farrar, G. J. Autosomal dominant retinitis pigmentosa: no evidence for nonallelic genetic heterogeneity on 3q. Am. J. Hum. Genet. 52: 319-326, 1993. [PubMed: 8430695]
Lem, J., Krasnoperova, N. V., Calvert, P. D., Kosaras, B., Cameron, D. A., Nicolo, M., Makino, C. L., Sidman, R. L. Morphological, physiological, and biochemical changes in rhodopsin knockout mice. Proc. Nat. Acad. Sci. 96: 736-741, 1999. [PubMed: 9892703] [Full Text: https://doi.org/10.1073/pnas.96.2.736]
Lester, D. H., Inglehearn, C. F., Bashir, R., Ackford, H., Esakowitz, L., Jay, M., Bird, A. C., Wright, A. F., Papiha, S. S., Bhattacharya, S. S. Linkage to D3S47 (C17) in one large autosomal dominant retinitis pigmentosa family and exclusion in another: confirmation of genetic heterogeneity. Am. J. Hum. Genet. 47: 536-541, 1990. [PubMed: 2393026]
Li, T., Sandberg, M. A., Pawlyk, B. S., Rosner, B., Hayes, K. C., Dryja, T. P., Berson, E. L. Effect of vitamin A supplementation on rhodopsin mutants threonine-17-to-methionine and proline-347-to-serine in transgenic mice and in cell cultures. Proc. Nat. Acad. Sci. 95: 11933-11938, 1998. [PubMed: 9751768] [Full Text: https://doi.org/10.1073/pnas.95.20.11933]
McInnes, R. R., Bascom, R. A. Retinal genetics: a nullifying effect for rhodopsin. Nature Genet. 1: 155-157, 1992. [PubMed: 1303226] [Full Text: https://doi.org/10.1038/ng0692-155]
McWilliam, P., Farrar, G. J., Kenna, P., Bradley, D. G., Humphries, M. M., Sharp, E. M., McConnell, D. J., Lawler, M., Sheils, D., Ryan, C., Stevens, K., Daiger, S. P., Humphries, P. Autosomal dominant retinitis pigmentosa (ADRP): localization of an ADRP gene to the long arm of chromosome 3. Genomics 5: 619-622, 1989. [PubMed: 2613244] [Full Text: https://doi.org/10.1016/0888-7543(89)90031-1]
Naash, M. I., Hollyfield, J. G., Al-Ubaidi, M. R., Baehr, W. Simulation of human autosomal dominant retinitis pigmentosa in transgenic mice expressing a mutated murine opsin gene. Proc. Nat. Acad. Sci. 90: 5499-5503, 1993. [PubMed: 8516292] [Full Text: https://doi.org/10.1073/pnas.90.12.5499]
O'Reilly, M., Palfi, A., Chadderton, N., Millington-Ward, S., Ader, M., Cronin, T., Tuohy, T., Auricchio, A., Hildinger, M., Tivnan, A., McNally, N., Humphries, M. M., Kiang, A.-S., Humphries, P., Kenna, P. F., Farrar, G. J. RNA interference-mediated suppression and replacement of human rhodopsin in vivo. Am. J. Hum. Genet. 81: 127-135, 2007. [PubMed: 17564969] [Full Text: https://doi.org/10.1086/519025]
Oh, K. T., Weleber, R. G., Lotery, A., Oh, D. M., Billingslea, A. M., Stone, E. M. Description of a new mutation in rhodopsin, pro23 to ala, and comparison with electroretinographic and clinical characteristics of the pro23-to-his mutation. Arch. Ophthal. 118: 1269-1276, 2000. [PubMed: 10980774] [Full Text: https://doi.org/10.1001/archopht.118.9.1269]
Olsson, J. E., Gordon, J. W., Pawlyk, B. S., Roof, D., Hayes, A., Molday, R. S., Mukai, S., Cowley, G. S., Berson, E. L., Dryja, T. P. Transgenic mice with a rhodopsin mutation (Pro23His): a mouse model of autosomal dominant retinitis pigmentosa. Neuron 9: 815-830, 1992. [PubMed: 1418997] [Full Text: https://doi.org/10.1016/0896-6273(92)90236-7]
Olsson, J. E., Samanns, C., Jimenez, J., Pongratz, J., Chand, A., Watty, A., Seuchter, S. A., Denton, M., Gal, A. Gene of type II autosomal dominant retinitis pigmentosa maps on the long arm of chromosome 3. Am. J. Med. Genet. 35: 595-599, 1990. [PubMed: 2333895] [Full Text: https://doi.org/10.1002/ajmg.1320350434]
Organisciak, D. T., Darrow, R. M., Barsalou, L., Kutty, R. K., Wiggert, B. Susceptibility to retinal light damage in transgenic rats with rhodopsin mutations. Invest. Ophthal. Vis. Sci. 44: 486-492, 2003. [PubMed: 12556372] [Full Text: https://doi.org/10.1167/iovs.02-0708]
Pannarale, M. R., Grammatico, B., Iannaccone, A., Forte, R., De Bernardo, C., Flagiello, L., Vingolo, E. M., Del Porto, G. Autosomal-dominant retinitis pigmentosa associated with an arg-135-trp point mutation of the rhodopsin gene: clinical features and longitudinal observations. Ophthalmology 103: 1443-1452, 1996. [PubMed: 8841304] [Full Text: https://doi.org/10.1016/s0161-6420(96)30485-5]
Patrizi, C., Llado, M., Benati, D., Iodice, C., Marrocco, E., Guarascio, R., Surace, E. M., Cheetham, M. E., Auricchio, A., Recchia, A. Allele-specific editing ameliorates dominant retinitis pigmentosa in a transgenic mouse model. Am. J. Hum. Genet. 108: 295-308, 2021. [PubMed: 33508235] [Full Text: https://doi.org/10.1016/j.ajhg.2021.01.006]
Ponjavic, V., Abrahamson, M., Andreasson, S., Ehinger, B., Fex, G. Autosomal dominant retinitis pigmentosa with a rhodopsin mutation (arg-135-trp): disease phenotype in a Swedish family. Acta Ophthal. Scand. 75: 218-223, 1997. [PubMed: 9197578] [Full Text: https://doi.org/10.1111/j.1600-0420.1997.tb00129.x]
Rosenfeld, P. J., Cowley, G. S., Hahn, L. B., Sandberg, M. A., Berson, E. L., Dryja, T. P. A null mutation within the rhodopsin gene in a family with autosomal recessive retinitis pigmentosa. (Abstract) Invest. Ophthal. Vis. Sci. 33: 1397, 1992.
Rosenfeld, P. J., Cowley, G. S., McGee, T. L., Sandberg, M. A., Berson, E. L., Dryja, T. P. A null mutation in the rhodopsin gene causes rod photoreceptor dysfunction and autosomal recessive retinitis pigmentosa. Nature Genet. 1: 209-213, 1992. [PubMed: 1303237] [Full Text: https://doi.org/10.1038/ng0692-209]
Sakami, S., Maeda, T., Bereta, G., Okano, K., Golczak, M., Sumaroka, A., Roman, A. J., Cideciyan, A. V., Jacobson, S. G., Palczewski, K. Probing mechanisms of photoreceptor degeneration in a new mouse model of the common form of autosomal dominant retinitis pigmentosa due to P23H opsin mutations. J. Biol. Chem. 286: 10551-10567, 2011. [PubMed: 21224384] [Full Text: https://doi.org/10.1074/jbc.M110.209759]
Sandberg, M. A., Rosner, B., Weigel-DiFranco, C., Dryja, T. P., Berson, E. L. Disease course of patients with X-linked retinitis pigmentosa due to RPGR gene mutations. Invest. Ophthal. Vis. Sci. 48: 1298-1304, 2007. [PubMed: 17325176] [Full Text: https://doi.org/10.1167/iovs.06-0971]
Van Schil, K., Karlstetter, M., Aslanidis, A., Dannhausen, K., Azam, M., Qamar, R., Leroy, B. P., Depasse, F., Langmann, T., De Baere, E. Autosomal recessive retinitis pigmentosa with homozygous rhodopsin mutation E150K and non-coding cis-regulatory variants in CRX-binding regions of SAMD7. Sci. Rep. 6: 21307, 2016. [PubMed: 26887858] [Full Text: https://doi.org/10.1038/srep21307]
White, D. A., Fritz, J. J., Hauswirth, W. W., Kaushal, S., Lewin, A. S. Increased sensitivity to light-induced damage in a mouse model of autosomal dominant retinal disease. Invest. Ophthal. Vis. Sci. 48: 1942-1951, 2007. Note: Erratum: Invest. Ophthal. Vis. Sci. 48: 3436 only, 2007. [PubMed: 17460245] [Full Text: https://doi.org/10.1167/iovs.06-1131]