Alternative titles; symbols
HGNC Approved Gene Symbol: RHO
SNOMEDCT: 715562001;
Cytogenetic location: 3q22.1 Genomic coordinates (GRCh38): 3:129,528,639-129,535,344 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q22.1 | Night blindness, congenital stationary, autosomal dominant 1 | 610445 | Autosomal dominant | 3 |
| Retinitis pigmentosa 4, autosomal dominant or recessive | 613731 | Autosomal dominant; Autosomal recessive | 3 | |
| Retinitis punctata albescens | 136880 | Autosomal dominant; Autosomal recessive | 3 |
Visual pigments are the light-absorbing molecules that mediate vision. They consist of an apoprotein, opsin, covalently linked to 11-cis-retinal or, rarely, 11-cis-dehydroretinal. Visual pigments are integral membrane proteins that reside in the plasma and disc membranes of the photoreceptor outer segment. When a photon is absorbed by a visual pigment, retinal is isomerized from the 11-cis to the all-trans configuration, triggering conformational changes in the attached apoprotein that create or unveil an enzymatic site on its cytosolic face. An enzymatically active visual pigment catalyzes the conversion of several hundred second messengers from the inert to the active state, the first step in a cascade of enzymatic reactions that ultimately produces a neural signal. Rhodopsin is the visual pigment of photoreceptors with rod-shaped outer segments, or retinal rods. Rhodopsin mediates vision in dim light and absorbs maximally at 495 nm (summary by Nathans et al., 1986).
Nathans and Hogness (1984) isolated and sequenced the gene encoding human rhodopsin. The deduced 348-amino acid protein has 7 transmembrane domains, with a luminal N terminus and a cytoplasmic C terminus. The cytoplasmic face of rhodopsin, which is made up of 3 loops and the C-terminal tail, contains the catalytic site that promotes GTP-GDP exchange by transducin (see 139330) and several putative sites for light-dependent phosphorylation by rhodopsin kinase (GRK1; 180381). Rhodopsin also has 2 sites for N-glycosylation, and lys296 is the site for 11-cis-retinal attachment. Nathans et al. (1986) found that the deduced amino acid sequences of the 3 visual color pigments, OPN1SW (613522), OPN1MW (300821), and OPN1LW (300822), share about 41% identity with rhodopsin.
Using SDS-PAGE immunoblot analysis of detergent-soluble and -insoluble extracts from transfected HEK293 cells, Illing et al. (2002) found that, at low expression levels, human rhodopsin migrated predominantly as a detergent-soluble, diffuse band at a molecular mass of 40 to 43 kD. This species corresponded to monomeric, mature rhodopsin containing complex N-linked glycans. At higher expression levels, additional high molecular mass species of rhodopsin, suggestive of SDS-resistant multimers, were also detected. All of the monomeric rhodopsin partitioned into the detergent-soluble fraction, whereas the slower migrating forms partitioned into both detergent-soluble and -insoluble fractions.
Nathans and Hogness (1984) determined that the RHO gene contains 5 exons and spans 5.0 kb. The promoter region contains TATA and CAAT boxes, and the 3-prime end contains 2 possible polyadenylation sites.
By somatic cell hybrid studies, Nathans et al. (1986) assigned the human rhodopsin gene to chromosome 3q21-qter.
By Southern analysis of a set of mouse-hamster somatic hybrid cell lines using a partial cDNA clone for mouse opsin, Elliott et al. (1990) assigned the rhodopsin gene to mouse chromosome 6. This excludes it as a candidate gene for a number of forms of retinal degeneration that map to other mouse chromosomes. In interspecific backcrosses, the Rho locus was found to be 4 map units distal to the locus for the protooncogene Raf1 (164760) and 18 map units proximal to the locus for the protooncogene Kras2 (KRAS; 190070). In man, RAF1 and RHO are also syntenic but on opposite arms of chromosome 3.
Khorana (1992) reviewed structure-function relations in rhodopsin.
Borhan et al. (2000) traced the movement of the ligand/receptor complex in rhodopsin. Photoaffinity labeling of diazoketo-rhodopsin (Dk-Rh) and various bleaching intermediates showed that the ionone ring crosslinks to tryptophan-265 on helix F in Dk-Rh and batho-rhodopsin, and to alanine-169 on helix D in lumi-, meta-I-, and meta-II-rhodopsin intermediates. Borhan et al. (2000) suggested that it is likely that these movements involving a flip-over of the chromophoric ring trigger changes in cytoplasmic membrane loops, resulting in heterotrimeric G protein activation.
In eye bank eyes with age-related macular degeneration (see 153800), Ethen et al. (2005) demonstrated that a significant linear decline in both arrestin and rhodopsin content correlated with progressive worsening of ARMD in the macula. In contrast, the peripheral region showed no significant correlation between degree of ARMD and the content of either protein.
Using biochemical, physiologic, and genetic methods, Kennedy et al. (2001) examined the molecular events that occurred during dark adaptation and recovery in isolated and intact mouse retinas. They found that rhodopsin was multiply phosphorylated following light flash. Phosphorylation proceeded in an ordered fashion on 3 serines in the rhodopsin C-terminal tail, and phosphates accumulated for 10 to 15 minutes, after which they were dephosphorylated. Dark adaptation was associated with reduced rhodopsin transduction activity and rhodopsin phosphorylation. Reduction of all-trans retinal coincided with a shift from opsin phosphorylation to dephosphorylation.
Noorwez et al. (2004) showed that availability of 9- or 11-cis retinal increased the amount of opsin synthesized by transfected HEK293 cells, suggesting that retinal functions as a chaperone during opsin synthesis.
Palczewski et al. (2000) determined the structure of bovine rhodopsin from diffraction data extending to 2.8-angstrom resolution. The highly organized structure in the extracellular region, including a conserved disulfide bridge, forms a basis for the arrangement of the 7-helix transmembrane motif. The ground-state chromophore, 11-cis-retinal, holds the transmembrane region of the protein in the inactive conformation. Interactions of the chromophore with a cluster of key residues determine the wavelength of the maximum absorption. Changes in these interactions among rhodopsins facilitate color discrimination. Identification of a set of residues that mediate interactions between the transmembrane helices and the cytoplasmic surface, where G protein activation occurs, also suggests a possible structural change upon photoactivation. Bourne and Meng (2000) commented on the rhodopsin structure reported by Palczewski et al. (2000) and on its implications for understanding the structures and mechanisms of other G protein-coupled receptors.
Fotiadis et al. (2003) used infrared-laser atomic-force microscopy to reveal the native arrangement of rhodopsin, which forms paracrystalline arrays of dimers in mouse disc membranes.
Park et al. (2008) presented the crystal structure of ligand-free opsin from bovine retinal rod cells at 2.9-angstrom resolution. Compared to rhodopsin, opsin shows prominent structural changes in the conserved E(D)RY and NPxxY(x)5,6F regions and in TM5 to TM7. At the cytoplasmic side, TM6 is tilted outwards by 6 to 7 angstroms, whereas the helix structure of TM5 is more elongated and close to TM6. These structural changes, some of which were attributed to an active G protein-coupled receptor (GPCR) state, reorganize the empty retinal-binding pocket to disclose 2 openings that may serve the entry and exit of retinal.
Standfuss et al. (2011) presented the crystal structure at a resolution of 3 angstroms of the constitutively active rhodopsin mutant glu113 to gln in complex with a peptide derived from the carboxy terminus of the alpha-subunit of the G protein transducin (139330). The protein is in an active conformation that retains retinal in the binding pocket after photoactivation.
In patients with autosomal dominant retinitis pigmentosa mapping to chromosome 3q (RP4; 613731), Dryja et al. (1990) identified a 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%).
Franke et al. (1990) used induced mutations in rhodopsin to study the functional significance of the several parts of the molecule.
Sung et al. (1991) investigated the functional significance of 13 mutant rhodopsins responsible for autosomal dominant retinitis pigmentosa by transfection of cloned cDNA into tissue culture cells. At least 2 classes of biochemical defects were demonstrated.
In the original family with autosomal dominant retinitis pigmentosa linked to 3q (McWilliam et al., 1989), Farrar et al. (1992) demonstrated an arg207-to-met mutation (180380.0030) in the RHO gene.
McInnes and Bascom (1992) presented a diagram of the molecular structure of rhodopsin showing the site of the mutations identified in RP. Pro347 (with a CpG dinucleotide) is a mutation hotspot with 3 mutations: P347R (180380.0020), P347L (180380.0002), and P347S (180380.0003). McInnes and Bascom (1992) also presented a diagram of the rod photoreceptor outer segment and adjacent retinal pigment epithelial (RPE) cell. They illustrated the localization of rhodopsin, peripherin/rds (179605), and other photoreceptor candidate genes being examined in RP patients, including the alpha, beta, and gamma subunits of cyclic GMP phosphodiesterase (180071, 180072, 180073).
Using transfected HEK cells, Chuang et al. (2004) demonstrated that arg135 mutant rhodopsins (R135L, 180380.0011; R135W, 180380.0012; and R135G) are hyperphosphorylated and bind with high affinity to visual arrestin (181031). Mutant rhodopsin recruited the cytosolic arrestin to the plasma membrane, and the rhodopsin-arrestin complex was internalized into the endocytic pathway. Furthermore, the rhodopsin-arrestin complexes altered the morphology of endosomal compartments and severely damaged receptor-mediated endocytic functions. Because the biochemical and cellular defects of arg135 mutant rhodopsins are distinct from those previously described for class I and class II RP mutations, Chuang et al. (2004) proposed that they be named class III, and suggested that impaired endocytic activity may underlie the pathogenesis of RP caused by class III rhodopsin mutations.
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 4-generation family (RPT65) segregating autosomal dominant RP in which no mutations were found by multiplex PCR with next-generation sequencing in 11 genes where most adRP-causing mutations had been reported, de Sousa Dias et al. (2015) used a trio approach with whole-exome sequencing to find variants that were present in 2 affected family members but absent in an unaffected member. The only variant identified that segregated with RP in the family was a c.307G-A transition (G103R) in the RP-unrelated gene COL6A6 (616613). Because the COL6A6 gene is located only 1 Mb away from RHO, de Sousa Dias et al. (2015) performed MPLA analysis to determine whether there was an abnormal copy number of genomic DNA sequences at the RHO locus. They found a nearly 30% reduction in one probe that targets exon 5, suggesting a deletion at that locus. Direct genomic sequencing of the complete RHO gene revealed an 827-bp deletion (g.9281_10108del) beginning at intron 4 and encompassing all of exon 5 and 28 bp of the 3-prime UTR. The deletion was present in all patients and carriers of the COL6A6 genetic variant, showing the linkage between both variants. Unaffected members of the family did not carry either of these genetic variants. Carriers of the RHO deletion showed variable clinical status, and 2 of these carriers had not previously been diagnosed with RP.
In a Turkish brother and sister with an unusual RP phenotype, in which nummular intraretinal pigment deposits were observed in addition to the classic spicular pigmentation, 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). The authors suggested that the nummular pigment deposits observed in the affected sibs might be attributed to modifying genetic factors such as the SAMD7 variants.
Sung et al. (1993) reviewed rhodopsin mutations responsible for autosomal dominant retinitis pigmentosa and studied the functional characteristics of many of them by introducing specific mutations into human rhodopsin cDNA by site-directed mutagenesis and producing the encoded proteins by transfection of a human embryonic kidney cell line.
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.
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.
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, see 302060) 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.
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 (180380.0001). 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.
Nie et al. (1996) generated transgenic mice containing a reporter gene located downstream of a 100-bp sequence highly conserved in the DNA upstream of the rhodopsin gene. They showed that the sequence behaves as a tissue-specific enhancer of transcription but that it appears not to be required for rhodopsin expression gradients across the retina.
Mendez et al. (2000) used transgenic and electrophysiologic methods to dissect functionally the role of the multiple phosphorylation sites during deactivation of rhodopsin in intact mouse rods. Mutant rhodopsins bearing 0, 1 (S338), or 2 (S334/S338) phosphorylation sites generated single-photon responses with greatly prolonged, exponentially distributed durations. Responses from rods expressing mutant rhodopsins bearing more than 2 phosphorylation sites declined along smooth, reproducible time courses; the rate of recovery increased with increasing numbers of phosphorylation sites. Mendez et al. (2000) concluded that multiple phosphorylation of rhodopsin is necessary for rapid and reproducible deactivation.
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.
Mice with an inactivated Rpe65 (180069) or Rho gene lack the visual pigment rhodopsin. Grimm et al. (2000) exposed both groups of mice to bright light. They 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 (164810) and Jun (165160) heterodimers. The level of Fos mRNA expressed in retinas Rpe65 -/- mice was 24% that of wildtype controls. In contrast, both wildtype and Rpe65 -/- mice expressed Jun mRNA at comparable levels.
Rhodopsin is essential for photoreceptor morphogenesis; photoreceptors lacking rhodopsin degenerate in humans, mice, and Drosophila. Chang and Ready (2000) reported that transgenic expression of a dominant-active Drosophila Rho guanosine triphosphatase, Rac1 (602048), rescued photoreceptor morphogenesis in rhodopsin null mutants. Expression of dominant-negative Rac1 resulted in a phenotype similar to that seen in rhodopsin null mutants. Rac1 was localized in a specialization of the photoreceptor cortical actin cytoskeleton, which was lost in rhodopsin null mutants. Thus, rhodopsin appears to organize the actin cytoskeleton through RAC1, contributing a structural support essential for photoreceptor morphogenesis.
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.
Excessive phototransduction signaling is thought to be involved in light-induced and inherited retinal degeneration. Using knockout mice with defects in rhodopsin shut-off and transducin signaling, Hao et al. (2002) showed that 2 different pathways of photoreceptor-cell apoptosis are induced by light. Bright light induces apoptosis that is independent of transducin and accompanied by induction of the transcription factor AP-1. By contrast, low light induces an apoptotic pathway that requires transducin. Hao et al. (2002) also provided evidence that additional genetic factors regulate sensitivity to light-induced damage. Jacobson and McInnes (2002) commented on the demonstration by Hao et al. (2002) of 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.
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.
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.
Alloway et al. (2000) demonstrated the existence of stable, persistent complexes between rhodopsin and its regulatory protein arrestin (181031) in several different retinal degeneration mutants in Drosophila. Elimination of these rhodopsin-arrestin complexes by removing either rhodopsin or arrestin rescues the degeneration phenotype. Furthermore, Alloway et al. (2000) showed that the accumulation of these complexes triggers apoptotic cell death and that the observed retinal degeneration requires the endocytic machinery. Thus, the endocytosis of rhodopsin-arrestin complexes may be a molecular mechanism for the initiation of retinal degeneration. Alloway et al. (2000) proposed that an identical mechanism may be responsible for the pathology found in a subset of human retinal degenerative disorders.
Kiselev et al. (2000) uncovered the pathway by which activation of rhodopsin in Drosophila mediates apoptosis through a G protein-independent mechanism. They found that the process involves the formation of membrane complexes of phosphorylated, activated rhodopsin and its inhibitory protein arrestin, and subsequent clathrin-dependent endocytosis of these complexes into a cytoplasmic compartment.
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.
Sakami et al. (2011) found that transgenic mice expressing mouse opsin with the P23H mutation developed retinal degeneration similar to the human disease, with outer segment disorganization and progressive functional deficits beginning in the rod photoreceptor system. P23H protein was inadequately glycosylated and degraded. It did not accumulate in the endoplasmic reticulum but disrupted the rod photoreceptor disks and caused perpendicularly oriented elongated discs. Retinal degeneration in adult transgenic mice appeared to be mainly due to necrosis.
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. 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.
Murray et al. (2015) observed that allele-specific antisense oligonucleotide (ASO)-mediated knockdown of mutant P23H rhodopsin expression slowed the rate of photoreceptor degeneration and preserved the function of photoreceptor cells in eyes of the P23H rhodopsin transgenic rat. The authors suggested that ASO treatment is a potentially effective treatment for RP.
In 17 of 148 unrelated patients with retinitis pigmentosa (see RP4; 613731) and none of 102 unaffected individuals, Dryja et al. (1990) found a heterozygous C-to-A transversion in codon 23 (corresponding to a proline-23-to-histidine substitution) in the RHO gene. This finding, coupled with the fact that the proline normally present at position 23 is highly conserved among the opsins and related G-protein receptors, indicates that the mutation is the cause of one form of autosomal dominant retinitis pigmentosa. Judging from the pattern of polymorphisms within the gene, i.e., haplotypes, the codon 23 mutation appears to have been derived from a single ancestor. Whereas the pro23-to-his mutation accounts for approximately 12% of American ADRP patients (Dryja et al., 1990), Farrar et al. (1990) found it in none of the affected individuals from 91 European pedigrees.
Berson et al. (1991) found that 17 unrelated ADRP patients (mean age, 37 years) with the P23H mutation had significantly better visual acuity and larger electroretinographic amplitudes than 131 unrelated ADRP patients (mean age, 32 years) without this mutation. They found that these 17 patients, as well as 12 affected relatives in 4 of the families, showed interfamilial and intrafamilial variability with respect to the severity of their ocular disease. This suggested the operation of other factors. At least one other factor was indeed deduced by Heckenlively et al. (1991). They found the P23H mutation in 2 males with sectoral retinitis pigmentosa who had a striking history of light exposure. One was a 28-year-old man who had worked for 8 years as a lifeguard at a beach during the summers and a ski instructor during the winters, skiing up to 150 days per year. The sectoral changes in the retina involved that part with the most light exposure. In contrast, his 52-year-old mother and his maternal grandfather had pigmentary retinopathy but were essentially asymptomatic. The mother and grandfather had lived all their lives in the Pacific Northwest where there is less direct sunlight. A second patient was a 27-year-old man who had served 3 tours of duty at sea in the Navy as well as fireguard duty in dry dock overseeing the welding operations on the floor of the ship. Several relatives had very mild RP. Heckenlively et al. (1991) suggested phototoxicity as a factor in RP due to the P23H mutation.
Illing et al. (2002) studied the effect of the P23H mutation on the structure and stability of rhodopsin transfected into HEK293 cells. Wildtype rhodopsin was expressed as a monomeric protein containing complex N-linked glycans. P23H rhodopsin was retained within the endoplasmic reticulum, contained unmodified oligosaccharides, and formed high molecular mass oligomeric species due to its nonnative conformation. Using fluorescence resonance energy transfer, Illing et al. (2002) observed that the misfolded P23H protein was degraded by the ubiquitin proteasome system (see 602175) and that, unlike wildtype rhodopsin, expression of P23H resulted in a generalized impairment of the ubiquitin proteasome system, suggesting a mechanism for photoreceptor degeneration. They noted that other aggregation-prone proteins associated with degenerative diseases of the CNS also lead to generalized impairment of the ubiquitin proteasome system.
Noorwez et al. (2004) found that little P23H opsin localized to the cell surface of transfected HEK293 cells in the absence of added 9- or 11-cis-retinal. P23H retinal showed an 8-nm blue shift in the visible absorption maximum with both 9- and 11-cis retinal, suggesting that the structure of P23H rhodopsin is different from that of wildtype rhodopsin. 9- and 11-cis P23H rhodopsins also showed reduced thermal stability and increased hydroxylamine sensitivity compared with wildtype rhodopsin.
Using fluorescence resonance energy transfer and coprecipitation studies, Rajan and Kopito (2005) showed that P23H rhodopsin formed a high molecular mass, detergent-insoluble complex with wildtype rhodopsin, resulting in ubiquitination and degradation of the wildtype protein as well as the P23H mutant. Rajan and Kopito (2005) hypothesize that the effect of P23H on the wildtype protein may underlie the dominant inheritance of ARDP.
In 8 of 28 unrelated patients with retinitis pigmentosa (see RP4; 613731), Dryja et al. (1990) found 2 heterozygous mutations involving C-to-T transitions at separate nucleotides of codon 347 in the RHO gene. One was a change in the second position, from CCG to CTG, which resulted in substitution of leucine for proline (P347L). Also see 180380.0003.
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.
In 1 of 28 unrelated patients with RP (see RP4; 613731), Dryja et al. (1990) identified a heterozygous transition from C-to-T involving the first nucleotide of codon 347 in the RHO gene, a change from CCG to TCG, which resulted in substitution of serine for proline.
To explore the pathogenic mechanism of dominant mutations that affect the C-terminus of rhodopsin and cause retinitis pigmentosa, Li et al. (1996) generated 5 lines of transgenic mice carrying the P347S mutation. The severity of photoreceptor degeneration correlated with the levels of transgene expression in these lines. Visual function as measured by the electroretinogram (ERG) was approximately normal at an early stage when there was little histologic evidence for photoreceptor degeneration, but it deteriorated as photoreceptors degenerated. Immunocytochemical staining showed the mutant rhodopsin residing predominantly in the outer segments before histologically evident degeneration, a finding supported by quantitation of signal intensities in different regions of the photoreceptor cells by confocal microscopy. A distinct histopathologic abnormality was the accumulation of submicrometer-sized vesicles extracellularly near the junction between inner and outer segments. The extracellular vesicles were bound by a single membrane that apparently contained rhodopsin, as revealed by ultrastructural immunocytochemical staining with anti-rhodopsin antibodies. The outer segments, although shortened, contained well-packed discs. Proliferation of the endoplasmic reticulum as reported in Drosophila expressing dominant rhodopsin mutations was not observed. Li et al. (1996) speculated that the accumulation of rhodopsin-laden vesicles probably represented aberrant transport of rhodopsin from the inner segments to the nascent disc membranes of the outer segments. They commented that photoreceptor degeneration may occur because of failure to renew outer segments at a normal rate, thereby leading to a progressive shortening of outer segments, or because of the loss of cellular contents to the extracellular space, or because of both.
In 1 of 28 patients with RP (see RP4; 613731), Dryja et al. (1990) found a heterozygous C-to-G transversion in the second nucleotide of codon 58 of the RHO gene. This change, ACG to AGG, resulted in replacement of a neutral threonine residue in the first transmembrane domain of the rhodopsin molecule with the charged amino acid arginine (T48R). With this base change, the DNA sequence could be cleaved with DdeI. Dryja et al. (1990) screened 150 unrelated patients as well as 106 normal subjects for the presence of a DdeI site at this location; only the original patient had the novel site.
Fishman et al. (1991) suggested that a clinically recognizable phenotype is associated with this specific gene defect: the features included a regional predilection for pigmentary changes in the inferior and inferonasal parts of the retina, as well as field impairment predominantly in the superior hemisphere. Characteristic electroretinographic recordings and psychophysical threshold profiles also helped to identify this phenotype that, on a relative basis, causes less severe photoreceptor cell functional impairment than occurs in many other subtypes of RP.
In affected members of a family segregating autosomal dominant RP, Jacobson et al. (1991) identified the T58R mutation in the RHO gene. These patients as well as one with the T17M (180380.0006) mutation had altitudinal visual field defects with less impaired rod and cone function in the inferior than in the superior field, but rod adaptation was much faster in the patients with the T58R mutation than in the patient with the T17M mutation.
Inglehearn et al. (1993) indicated that family 20 of Olsson et al. (1990), which had been thought to have an RHO-unlinked chromosome 3q form of RP, in fact had an ACG (thr) to AGG (arg) mutation at codon 58 of the RHO gene.
In affected members of a family segregating autosomal dominant RP (RP4; 613731), Inglehearn et al. (1991) identified a heterozygous in-frame 3-bp deletion in exon 4 of the RHO gene, which deleted 1 of the 2 isoleucine residues at codons 255 and 256. The mutation was not found in 30 other unrelated ADRP families. The deletion had occurred in a sequence involving a run of three 3-bp repeats. The mechanism by which the mutation arose may be the same as that which creates length variation in so-called mini- and microsatellites.
See Sung et al. (1991). Also see Jacobson et al. (1991) and 180380.0004.
See Sung et al. (1991).
See Sung et al. (1991).
See Sung et al. (1991).
See Sung et al. (1991).
In 2 patients with autosomal dominant RP (RP4; 613731), Sung et al. (1991) identified an arg135-to-leu (R135L) mutation in the RHO gene. Also see 180380.0012 and Jacobson et al. (1991).
In a 6-generation Swedish family segregating autosomal dominant RP, Andreasson et al. (1992) identified a 404G-T transversion in exon 2 of the RHO gene, leading to an R135L substitution. All affected members of this family had early-onset night blindness and substantial visual field losses as teenagers. Even in the youngest patients, fundus pigmentation was seen together with severe constriction of the retinal blood vessels in all quadrants of the fundus. Andreasson et al. (1992) concluded that the R135L mutation may cause a more rapidly progressive form of RP than other mutations.
In 2 patients with autosomal dominant RP (RP4; 613731), Sung et al. (1991) identified an arg135-to-trp (R135W) mutation in the RHO gene.
In 2 families with autosomal dominant RP, Jacobson et al. (1991) identified the R135W mutation in the RHO gene. All members of these families and of another family with an R135L mutation (180380.0011) showed loss of rod function diffusely across the visual field with some residual cone function on dark-adapted perimetry, and even at relatively young ages had undetectable rod and cone electroretinograms.
In a large Sicilian pedigree with autosomal dominant RP, Pannarale et al. (1996) identified a 403C-T transition in exon 2 of the rhodopsin gene, producing an R135W mutation in the rhodopsin molecule. Patients demonstrated measurable ERG activity until at least 18 years of age, although it was reduced to 2 to 4% of normal. 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 at codon 135 of rhodopsin appears to have an unusually high progression rate and to yield an extremely poor prognosis.
In a 4-generation Swedish family segregating autosomal dominant retinitis pigmentosa, Ponjavic et al. (1997) identified the R135W mutation. Using full-field ERG, the authors documented a severe form of RP in affected members, similar to the phenotype observed by Andreasson et al. (1992) in a family with the R135L mutation (see 180380.0011). 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.
Souied et al. (1996) screened for mutations in the rhodopsin, peripherin/RDS (179605), and ROM1 (180721) genes in a family affected with retinitis punctata albescens (136880). One member of the family showed features typical of retinitis pigmentosa. Therefore, they analyzed the apolipoprotein E (APOE; 107741) gene to elucidate the unusual intrafamilial heterogeneity. The coding sequences of the first 3 genes were analyzed with a combination of SSCP1 and direct sequence analysis. The arg135-to-trp (R135W) mutation in RHO was observed in all affected members of the family and no mutation was detected in RDS or ROM1. The epsilon-4 allele of the APOE gene appeared to cosegregate with the albescens phenotype in this family. A mother and 2 daughters had retinitis punctata albescens and the APOE4 allele. A brother of the mother had retinitis pigmentosa alone. Souied et al. (1996) reported that they had found the R135W RHO mutation in 3 (5%) of 58 subjects with autosomal dominant RP.
See Sung et al. (1991). Farrar et al. (1991) found this mutation in 2 families of Celtic origin living in Ireland. The patients showed early onset of autosomal dominant RP (RP4; 613731). Night blindness and fundal abnormalities were present in the first and second decades. By the second and third decades, patients had extinguished rod and cone responses.
See Sung et al. (1991).
See Sung et al. (1991). In members of a family segregating autosomal dominant RP (RP4; 613731), Jacobson et al. (1991) identified heterozygosity for the gln344-to-ter (Q344X) mutation in the RHO gene. The authors noted an unusual phenotype in 3 younger members with the mutation who were asymptomatic and clinically unaffected: visual acuity, cone electroretinogram amplitude, and cone perimetry were normal at a time when rod function was abnormal. Older patients in this family had a more advanced stage of disease indistinguishable from other forms of severe RP, but they reported that they had excellent night and day vision in their youth.
This mutation is classified as a type 1 mutation by the criteria of Sung et al. (1994) in that protein is produced at high levels, accumulates in the plasma membrane, and binds efficiently to 11-cis retinal in vitro to form photolabile pigments. As are most class 1 mutants, this mutation maps very closely to the carboxy terminus. Sung et al. (1994) studied the gln344-to-ter (Q344X) mutation in detail. In transfected tissue culture cells, the mutant protein shows normal light-dependent activation of the photoreceptor G protein (transducin) and is a normal light-dependent substrate for rhodopsin kinase. Transgenic mice show nearly normal light responses by suction electrode recordings. However, the mutant rhodopsin abnormally accumulates in the plasma membrane of the photoreceptor cell body, as well as in the rod outer segment in which the wildtype protein is confined. Sung et al. (1994) suggested that the C terminus of rhodopsin is required for transport or retention in the outer segment. They further suggested that all class 1 rhodopsin mutants cause retinitis pigmentosa by improper localization of the rhodopsin, which otherwise functions normally.
In a family with autosomal dominant retinitis pigmentosa (RP4; 613731), Keen et al. (1991) observed change in codon 296 from AAG to GAG resulting in substitution of glutamic acid for lysine. The disorder in this family was distinguished by its particular severity, showing early onset of the disease and development of cataracts by the third or fourth decade of life. Two critical amino acids in rhodopsin are lys296, the site of attachment of retinal to the protein through a protonated Schiff base linkage, and glu113, the Schiff base counterion. Robinson et al. (1992) demonstrated that mutation in lys296 or in glu113 results in constitutive activation of opsin, as assayed by its ability to activate the G protein transducin in the absence of added chromophore. They concluded that opsin is constrained to an inactive conformation by a salt bridge between lys296 and glu113. The lys296-to-glu (K296E) mutation in the family reported by Keen et al. (1991) may represent degeneration of the photoreceptor cells as a result of persistent stimulation of the phototransduction pathway.
In a family with autosomal dominant retinitis pigmentosa (RP4; 613731), Keen et al. (1991) observed change in codon 190 from GAC to AAC resulting in substitution of asparagine for aspartic acid.
In a family with autosomal dominant retinitis pigmentosa (RP4; 613731), Keen et al. (1991) observed a heterozygous change in codon 211 from CAC to CCC, resulting in substitution of proline for histidine.
In a family with autosomal dominant retinitis pigmentosa (RP4; 613731), Keen et al. (1991) observed deletion of codons 68 to 71 in exon 1. These codons coded for leu--arg--thr--pro.
In a patient with autosomal dominant RP (RP4; 613731), Gal et al. (1991) demonstrated a CCG-to-CGG transversion in codon 347 predicting a pro-to-arg substitution. Two previous mutations in this codon had been reported: pro347-to-leu (180380.0002) and pro347-to-ser (180380.0003). Further evidence that this codon is prone to mutation is indicated by the fact that no linkage disequilibrium has been observed in patients with the pro347-to-leu mutation (Dryja et al., 1990), making it likely that this mutation arose independently more than one time.
In a patient with retinitis pigmentosa (RP4; 613731), Sheffield et al. (1991) identified heterozygosity for a G-to-A transition at codon 182 in exon 3 of the RHO gene, resulting in a gly182-to-ser (G182S) substitution.
In a patient with retinitis pigmentosa (RP4; 613731), Sheffield et al. (1991) identified heterozygosity for a C-to-T transition at codon 267 in exon 4 of the RHO gene, resulting in a pro267-to-leu (P267L) substitution.
Rosenfeld et al. (1992) hypothesized that null mutations of the rhodopsin gene might result in an autosomal recessive form of retinitis pigmentosa. Using single-strand conformation polymorphism (SSCP) analysis, they demonstrated a glu249-to-ter (E249X) (GAG to TAG) substitution in a 26-year-old French-Canadian female, the offspring of a consanguineous mating. The patient was homozygous for this mutation, predicted to result in absence of the fourth and fifth transmembrane domains and the retinal attachment site. The mutation should result in a functionally inactive protein. The proband had characteristic bone-spicule pigment around the midperiphery, undetectable rod ERG responses, and markedly reduced cone ERG responses. Rosenfeld et al. (1992) stated that both parents and 2 of 3 sibs were heterozygous for the mutation, and that all had normal ophthalmologic examinations and special tests. However, in their full report, Rosenfeld et al. (1992) stated that heterozygous carriers of the E249X mutation in fact had abnormality in rod photoreceptor function revealed by electroretinograms.
In a patient with autosomal dominant RP (RP4; 613731), Inglehearn et al. (1992) found a heterozygous CCC-to-CGC mutation in the RHO gene, resulting in substitution of arginine for proline at codon 53 (P53R).
In a family with autosomal dominant RP (RP4; 613731), Inglehearn et al. (1992) found a GGG-to-AGG mutation at codon 106 of the RHO gene, resulting in substitution of arginine for glycine (G106R).
Fishman et al. (1992) found a gly106-to-arg mutation in the RHO gene in 3 members of one family and in 1 person of another family. All affected persons had a distinctive phenotype that included a regional predilection for pigmentary changes to occur in the inferior retina as well as visual field impairment predominantly in the superior hemisphere. Substantial residual electroretinographic amplitudes with normal implicit times were also consistent with a form of 'sector' retinitis pigmentosa. Thus the specific mutation appears to be associated with a better visual prognosis.
In screening a group of 117 control persons without RP for the nonsense mutation E249X (180380.0023) in the RHO gene, Rosenfeld et al. (1992) found a 28-year-old female who was heterozygous for a different potential null mutation. After detection by SSCP analysis, direct sequencing of polymerase chain reaction (PCR)-amplified DNA from this person revealed a heterozygous G-to-T substitution at position 4335 within intron 4 of the rhodopsin gene. Since it is located at the canonical GT of the first 2 nucleotides of the splice donor sequence, the mutation is expected to interfere with normal processing of intron 4 and thus could alter the carboxy-terminal 36 amino acids of the rhodopsin molecule. The woman was found to have a reduction in rod sensitivity that was similar to the decrease observed in the carriers of the E249X mutation.
In 2 members of a family with autosomal dominant retinitis pigmentosa (RP4; 613731), Fishman et al. (1992) demonstrated a G-to-T mutation in the first nucleotide of codon 190 in the rhodopsin gene that resulted in an aspartate-to-tyrosine change. This GAC-to-TAC change was in the same nucleotide altered in the asp190-to-asn mutation (180380.0017). A family with the asp190-to-asn mutation showed a regional predilection for pigmentary retinal change and less severe functional impairment than did the patients with the asp190-to-tyr mutation.
In a family with retinitis pigmentosa (RP4; 613731) in which Humphries et al. (1992) had demonstrated linkage markers on 3q close to the gene encoding rhodopsin, Farrar et al. (1992) identified a T-to-G transversion in codon 207 resulting in the substitution of a methionine residue for an arginine residue. The clinical presentation of the family was unusual because of early onset of the disease. Affected members exhibited changes within the first decade of life, diffuse funduscopic disturbances, and extinguished rod photoreceptor cell responses as assessed by ERGs. ERG cone responses were retained until the third decade, although significantly reduced in amplitude and delayed in latency. With 2-color dark adaptometry, a diffuse loss of rod and cone photoreceptor sensitivity with a greater involvement of rods mirrored the ERG findings.
Kranich et al. (1993) used single-strand conformation polymorphism (SSCP) to detect altered PCR products of rhodopsin coding sequences in a large Australian pedigree with the 'sectorial' form of autosomal dominant RP (RP4; 613731). Direct sequencing demonstrated an A-to-G transition at codon 15 that predicted a change from asparagine to serine. Patients in this family demonstrated an asymmetric regional distribution of pigmentary changes and visual field loss with a relatively mild form of the disease and good central visual acuity into the fourth decade. 'Sector' RP has been described in patients with the following mutations: thr17-to-met (180380.0006), pro23-to-his (180380.0001), thr58-to-arg (180380.0004), gly106-to-arg (180380.0025), and gly182-to-ser (180380.0021).
Sullivan et al. (1993) described a 5-generation Australian family in which retinitis pigmentosa was associated with an inferior distribution of retinal pigmentary changes and predominantly superior visual field loss with relative preservation of electroretinographic amplitudes and good vision. The mutation was found to be in codon 15 of exon 1 where a single bp transversion (AAT to AGT) led to a serine-for-asparagine substitution. The mutation altered a glycosylation site in the intradiscal portion of the rhodopsin molecule.
Inspection of the pedigrees published by Kranich et al. (1993) and Sullivan et al. (1993) indicates identity; these reports do not represent recurrent mutation.
Farrar et al. (1992) demonstrated an ATG-to-AGG mutation in codon 207 of the RHO gene, leading to substitution of arg for met in the original family with retinitis pigmentosa linked to 3q (RP4; 613731) (McWilliam et al., 1989).
Reasoning that cases of congenital stationary night blindness without a rod a-wave might have a defect in the phototransduction pathway, Dryja et al. (1993) screened leukocyte DNA from a 34-year-old male who had reported night blindness since early life (CSNBAD1; 610445). He was heterozygous for a missense mutation, ala292-to-glu (A292E) in the RHO gene.
In affected members of a large Michigan kindred with autosomal dominant congenital stationary night blindness (CSNBAD1; 610445), Sieving et al. (1992) found heterozygosity for a single base substitution in codon 90 of rhodopsin: gly90 to asp (G90D).
Rao et al. (1994) pointed out that the ala292-to-glu (180380.0031) and gly90-to-asp mutations are located at sites in close proximity in the 3-dimensional structure of rhodopsin, suggesting that the constitutively activating mutations operate by a common molecular mechanism, disrupting a salt bridge between lys296 and the Schiff base counterion, glu113.
In an Indian family in which 5 of 9 sibs, the offspring of unaffected first-cousin parents, had retinitis pigmentosa (RP4; 613731), Kumaramanickavel et al. (1994) found a G-to-A transition at codon 150 of the RHP gene, predicted to lead to a change from glutamate (GAG) to lysine (AAG) in the gene product. The 4 patients available for study were homozygous for the E150K mutation and 2 of the unaffected 4 sibs were heterozygous. (In the diagram of the pedigree, the order of the sibs was deliberately scrambled to disguise the identity of the heterozygotes.) Glu150 forms part of the second cytoplasmic loop of rhodopsin. Of the more than 60 RP-causing rhodopsin mutations identified, only one, cys140-to-ser, was located in the cytoplasmic loop (Macke et al., 1993).
The E150K mutation in rhodopsin is located in its second cytoplasmic loop and is positioned at the rhodopsin dimer interface. Zhu et al. (2006) showed that neither global protein folding nor G-protein binding and activation by rhodopsin were significantly affected by the E150K mutation. However, E150K rhodopsin was aberrantly glycosylated and was retained in the cis/medial Golgi compartment. E150K rhodopsin did not alter plasma membrane targeting of wildtype rhodopsin in transfected HEK293 cells, and in the presence of excess wildtype rhodopsin, E150K rhodopsin was cotransported with wildtype rhodopsin through the trans-Golgi and delivered to the plasma membrane.
In a Turkish brother and sister with an unusual RP phenotype, Van Schil et al. (2016) identified homozygosity for the E150K mutation in the RHO gene. In addition, the sibs were homozygous for 4 noncoding variants in the SAMD7 gene (620493) that showed reduced activity compared to wildtype SAMD7 in luciferase experiments and electroporation assays in retinal explants. 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.
In a study of 122 patients with autosomal dominant retinitis pigmentosa (RP4; 613731), Vaithinathan et al. (1994) identified a G-to-C substitution in the RHO gene, leading to a change from glycine to arginine at position 51.
In a study of 122 patients with autosomal dominant retinitis pigmentosa (RP4; 613731), Vaithinathan et al. (1994) identified a C-to-A substitution in the RHO gene, leading to a change from cysteine to tyrosine at position 110.
In a study of 122 patients with autosomal dominant retinitis pigmentosa (RP4; 613731), Vaithinathan et al. (1994) identified a G-to-A substitution in the RHO gene, leading to a change from glycine to aspartic acid at position 114.
In a study of 122 patients with autosomal dominant retinitis pigmentosa (RP4; 613731), Vaithinathan et al. (1994) identified a C-to-A substitution in the RHO gene, leading to a change from alanine to glutamic acid at position 164.
In a study of 122 patients with autosomal dominant retinitis pigmentosa (RP4; 613731), Vaithinathan et al. (1994) identified a C-to-T substitution in the RHO gene, leading to a change from proline to serine at position 171.
In a study of 122 patients with autosomal dominant retinitis pigmentosa (RP4; 613731), Vaithinathan et al. (1994) identified an in-frame deletion of 3 bp in the RHO gene, corresponding to a cysteine at position 264.
In a study of 122 patients with autosomal dominant retinitis pigmentosa (RP4; 613731), Vaithinathan et al. (1994) identified a G-to-C substitution in the RHO gene, leading to a change from valine to leucine at position 345.
In a study of 122 patients with autosomal dominant retinitis pigmentosa (RP4; 613731), Vaithinathan et al. (1994) identified a C-to-A substitution in the RHO gene, leading to a change from proline to glutamine at position 347.
Dikshit and Agarwal (2001) looked for the presence or absence of codon 345 and 347 mutations in exon 5 of the RHO gene in 100 Indian patients with retinitis pigmentosa from 76 families, irrespective of the genetic category of RP. Surprisingly, in their sample the very widely reported highly frequent mutations at codon 347 (P-S/A/R/Q/L/T) were absent, while the val345-to-met mutation (180380.0044) was found in 3 affected members of 1 family with the autosomal dominant form of the disorder and in 1 sporadic case.
In an Irish family segregating an autosomal dominant form of CSNB (CSNBAD1; 610445), al-Jandal et al. (1999) found a thr94-to-ile (T94I) mutation in the RHO gene. Computer modeling suggested that constitutive activation of transducin by the altered rhodopsin protein may be a mechanism for disease causation in this family. Two other mutations within the rhodopsin gene had previously been reported in patients with CSNB; constitutive activation was proposed as a possible disease mechanism in these instances.
In 6 members of a family with autosomal dominant retinitis pigmentosa (RP4; 613731), Oh et al. (2000) identified a C-to-G change at nucleotide 1 of codon 23 of the rhodopsin gene, resulting in a pro23-to-ala substitution. The phenotype in this family was characterized by onset of symptoms in the second to fourth decades of life, loss of superior visual field with relatively well-preserved inferior fields, and mild nyctalopia.
Both val345-to-leu (180380.0040) and val345-to-met mutations in the RHO gene have been described as the basis of autosomal dominant retinitis pigmentosa (Dryja et al., 1991; Bunge et al., 1993). In a study of 100 patients from 76 Indian families with retinitis pigmentosa (RP4; 613731), Dikshit and Agarwal (2001) found the val345-to-met mutation in 3 cases in 1 family and in 1 sporadic case. Codon 347 (which is involved in 6 different types of missense mutation, P-S/A/R/Q/L/T) and codon 345 are located in the cytoplasmic domain of the protein. Theoretically, they are not involved in maintaining the tertiary structure of the protein, but mutations in them produce dysfunction and ultimately death of the photoreceptor cell.
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