ORPHA: 791; DO: 0110415;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xp11.3 | Retinitis pigmentosa 2 | 312600 | X-linked | 3 | RP2 | 300757 |
A number sign (#) is used with this entry because X-linked retinitis pigmentosa-2 (RP2) is caused by mutation in the RP2 gene (300757) on chromosome Xp11.
Retinitis pigmentosa is characterized by constriction of the visual fields, night blindness, and fundus changes, including 'bone corpuscle' lumps of pigment. RP unassociated with other abnormalities is inherited most frequently (84%) as an autosomal recessive, next as an autosomal dominant (10%), and least frequently (6%) as an X-linked recessive in the white U.S. population (Boughman et al., 1980).
For a general phenotypic description and a discussion of genetic heterogeneity of retinitis pigmentosa, see 268000.
The X-linked form of retinitis pigmentosa is also called choroidoretinal degeneration, or pigmentary retinopathy. The gyrate choroidal atrophy described by Waardenburg (1932) as X-linked was found on further study to be retinitis pigmentosa (Waardenburg et al., 1961). As pointed out in a review by Jacobson and Stephens (1962), there are some phenotypic differences between reported families. The genetic significance of these differences is unknown. There may be a fully recessive and an intermediate X-linked form. Affected males show typical 'bone corpuscle' clumps of pigment on funduscopic examination and progressive choroidal sclerosis leading to complete blindness.
Hoare (1965) described a choroidoretinal disorder in 10 males in 7 sibships who were offspring of sisters. The maternal grandfather of the affected males was probably also affected. The condition was detected in childhood. Some carrier women showed fundus abnormalities with visual impairment beginning in middle age and probably showing progression. The condition in males resembled retinitis pigmentosa in fundus picture and night blindness, but differed by the absence of annular scotoma, by early involvement of central vision, and by relatively little vascular change. In fact, many males with RP2 show choroidoretinal atrophy in the advanced stages (Bird, 1975).
In 21 females heterozygous for X-linked RP (XLRP), Ernst et al. (1981) found reduced flicker sensitivity over the whole frequency range where thresholds could be tested.
Bundey and Crews (1986) concluded that the likelihood of an isolated male with severe retinitis pigmentosa having the X-linked form is about 1 in 2; of 74 male index patients, 21 had X-linked disease. In the family reported by Heck (1963), some heterozygous females were fully affected and some showed only a blue-yellow color defect (a rare anomaly). 'Tapetal reflex' was not present. The type of retinal degeneration was variable, being pigmentary, nonpigmentary, or macular in different affected males. Cataract was present in 2 with pigmentary degeneration.
Fishman et al. (1988) profiled the clinical findings in 56 patients with X-linked retinitis pigmentosa from 35 families.
Ultrastructural observations suggested that the rod photoreceptors are severely affected by the mutation in this disorder. Because photoreceptors develop from ciliated progenitors, it has been suggested that the axoneme may play a role in the development of photoreceptors. For this reason, Hunter et al. (1988) studied sperm axoneme structure in 8 patients with X-linked retinitis pigmentosa. A significant increase in the percentage of abnormal sperm tails was observed. Similar observations have been reported in Usher syndrome (276900).
Kaplan et al. (1990) suggested that phenotypically there are 2 forms of X-linked RP: one form has very early onset with severe myopia (mean age of onset = 3.5 years; 1 SD = 0.05); the other form starts later with night blindness with or without mild myopia (mean age of onset = 10.6 years; 1 SD = 4.1). Kaplan et al. (1992) presented linkage evidence that the clinical form with early myopia as the initial symptom is associated with the RP2 gene, while the clinical form with later night blindness as the initial symptom is associated with the RP3 gene.
Friedrich et al. (1993) found on reexamination of 7 obligate carrier females and 6 daughters of obligate carriers whose linkage relationships suggested that they carried the RP2 gene that the phenotype varied from totally normal eyes through mild retinal changes to complete loss of vision.
Grover et al. (2000) evaluated the progression of visual impairment in carriers of X-linked recessive retinitis pigmentosa. They described the relationship between retinal findings at presentation and the extent of subsequent deterioration. They followed visual acuity, visual field, and electroretinograms (ERG) in 27 carriers of XLRP and described 4 grades of fundus findings from grade 0 (normal) to grade 3 (diffuse changes). They found that carriers of XLRP with only a tapetal-like retinal reflex (grade 1) at presentation were more likely to retain visual function than those with peripheral retinal pigmentation. Grover et al. (2000) concluded that these data are useful in counseling such carriers as to their visual prognosis.
In a study of 242 female carriers of X-linked RP, half of whom had RP2 or RP3, Comander et al. (2015) found that most carriers had mildly or moderately reduced visual function but rarely became legally blind. In most cases, obligate carriers could be identified by ERG testing. XLRP carrier ERG amplitudes and decay rates over time were on average half of those of affected men, consistent with the Lyon hypothesis of random X inactivation.
Grover et al. (2002) compared the extent of intraocular light scatter (straylight) in carriers of choroideremia (CHM; 303100) and the various forms of XLRP to clarify the relationship between photoreceptor cell degeneration and intraocular light scatter in hereditary retinal degenerations. The carriers of XLRP who had evidence of photoreceptor cell dysfunction (as determined by visual field loss and reduced electroretinogram amplitudes) had increased levels of intraocular straylight, whereas the carriers of CHM, who showed fundus abnormalities alone, in the absence of demonstrable photoreceptor cell dysfunction, had normal or minimally elevated levels of light scatter. The authors concluded that the clinical symptom of glare, often reported by patients with RP, results, at least in part, from increased intraocular straylight caused by alterations in the optical quality of the crystalline lens as a consequence of photoreceptor cell degeneration.
That the entity in the family reported by Hoare (1965) was identical to (or allelic with) that discussed in this entry was established by demonstration of identical linkage relationships (Bhattacharya et al., 1985; Jay, 1987). In linkage studies with the L1.28 probe (DXS7), Bhattacharya et al. (1984) found a maximum lod score of 7.89 at a distance of 3 cM (95% confidence limits 0-15).
Friedrich et al. (1985) also published data on linkage with L1.28 (DXS7) and C-banding heteromorphism. They concluded that the RP2 locus is close to the centromere. RP2 lies between the centromere and DXS7. The same group used centromeric heteromorphism to place Menkes disease (309400) close to the centromere.
Clayton et al. (1986) summarized the data to that time on linkage to DXS7. A maximum lod score of 14.01 at a theta of 0.08 was obtained. There was no evidence for heterogeneity of recombination fraction among the 13 families for which data were available. Wright et al. (1987) analyzed linkage against Xp markers. The portion of the chromosome distal to OTC was excluded as the location of RP2. The linkage observed with OTC was theta = 0.19 (lod = 3.61). The most closely linked DNA marker was DXS7 (theta = 0.09; lod = 8.66). Chen et al. (1987) found a more distal location of the RP locus in 3 large pedigrees which may have represented a separate disorder; heterozygotes showed the characteristic tapetal reflex. In this family, OTC and RP2 seemed to be tightly linked (lod = 10.64; theta = 0.00). It was presumably RP3 (300029) that Chen et al. (1987) were dealing with in this family. Litt et al. (1987) found no recombination of RP2 with DXS7 or with DXZ1, a centromeric site detected by an alpha-satellite probe. On the basis of a study of 20 kindreds, Wright et al. (1987) concluded that X-linked RP lies proximal to DXS7, which has been mapped to Xp11.3. Meitinger et al. (1989) demonstrated linkage to an informative hypervariable marker defining the DXS255 segment; theta = 0.07 at a maximum lod of 4.75. Farrar et al. (1988) contributed linkage data to the question of heterogeneity in X-linked RP. Chen et al. (1989) presented further data supporting the existence of 2 separate RP loci on Xp; by multipoint linkage analysis with 10 loci in 9 affected families, the mutation mapped telomeric to DXS7 in 7 and centromeric to DXS7 in 2. Microsatellites are stretches of tandemly repeated dinucleotides, such as poly(dGdT).(dCdA), which are widely distributed throughout eukaryotic genomes. Many microsatellites are hypervariable by reason of a variable number of dinucleotide repeats. Such polymorphisms can be studied by using PCR to amplify across the repeats and then resolving size differences (multiples of dinucleotides) in the PCR product by PAGE (Litt and Luty, 1989; Weber and May, 1989). Coleman et al. (1990) found that one such polymorphic microsatellite, DXS426, maps to Xp11.4-p11.22. They used this information for refinement of the location of the RP2 gene, which they concluded lies between DXS426 and DXS7. Wright et al. (1991) found no recombination with DXS255 (in Xp11.22) or TIMP (in Xp11.3-p11.23; 305370).
Friedrich et al. (1992) used DNA markers and the cytogenetic centromere marker for linkage mapping in a large Danish family. They found the highest location score for a site distal to DXS255 and proximal to the OTC locus. In comparison with the first large Danish family that Friedrich et al. (1985) had studied, the recombination fraction between the centromere and the proximal genetic marker on the short arm, DXS7, was 0.17, which corresponded to the distance 18 cM recorded by HGM10 (Keats et al., 1989). However, in the second Danish family (Friedrich et al., 1992), the pericentric recombination fraction was increased, leading them to speculate that the difference in the size and location of the centromeric heterochromatin was responsible. Involvement of centromeric heterochromatin in recombination is well known in Drosophila; recombination in the euchromatin near the centromere is usually reduced, the so-called centromere effect. Variability in the position and amount of heterochromatin was observed between the 2 families. Another finding of note in the second family was the presence of several blind female carriers and a few female carriers with no phenotypic signs on thorough ophthalmologic examination and full field electroretinography (Friedrich et al., 1992).
Thiselton et al. (1996) reported a defined localization for the RP2 gene to a 5-cM interval in Xp11.3-p11.23.
In 2 unrelated families in which males were affected with retinal dystrophy but had normal intellectual development, Delphin et al. (2012) performed linkage analysis followed by high-resolution oligonucleotide microarray and defined deletions on chromosome Xp11.3 in each family. In the first family, a 509-kb deletion encompassed the 3-prime end of the ZNF673 gene (300585) and the 5-prime half of the PHF16 gene (300618). The proband in the second family carried 2 neighboring 431-kb and 388-kb deletions; the centromeric deletion encompassed the 3-prime UTR of ZNF673 and intron 4 of RP2, whereas the telomeric deletion encompassed no known gene. Patients in the first family showed very similar age and mode of onset of the disease, exhibiting early severe myopia and macular rearrangements with preservation of the peripheral retina, but flat electroretinographic (ERG) responses before the age of 6 years. The proband in the second family presented at age 4 with jerk nystagmus, high bilateral myopia, diffuse retinal pigment epithelium (RPE) atrophy, and normal ERG recordings. By age 8, examination showed bull's eye macula with peripapillary atrophy, peripheral atrophic RPE with some pigmentary deposits and thin retinal vessels, central scotoma and constricted peripheral visual field, and severely altered photopic and scotopic ERG responses.
In 6 patients with X-linked retinitis pigmentosa, Schwahn et al. (1998) detected 6 different mutations in a novel gene (RP2; 300757).
In a cohort of North American families with X-linked retinitis pigmentosa, Mears et al. (1999) reported 5 protein truncation mutations of the RP2 gene. These were different from the 7 reported in European families by Schwahn et al. (1998), suggesting a high rate of new mutations and a lack of founder effect.
Chapple et al. (2000) identified putative sites for N-terminal acyl modification by myristoylation and palmitoylation in the RP2 protein, consistent with its primary localization in the plasma membrane in cultured cells. Mutations in residues potentially required for N-terminal acylation revealed that the palmitoyl moiety is responsible for targeting of the myristoylated protein from intracellular membranes to the plasma membrane. The ser6del mutation (300757.0001) interfered with targeting of the protein to the plasma membrane, suggesting to the authors that the ser6del mutation may cause XLRP because it prevents normal amounts of RP2 from reaching the correct cellular locale. The R118H mutation (300757.0003) did not have a similar effect on localization.
Miano et al. (2001) identified 5 novel mutations in RP2, each in a different XLRP family. These mutations included 3 missense mutations, a splice site mutation, and a single base insertion, which, because of a frameshift, led to a premature stop codon.
Grayson et al. (2002) examined the relationship between RP2, cofactor C (602971), and ARL3 (604695) in patient-derived cell lines and in the retina. Examination of lymphoblastoid cells from patients with the arg120-to-ter mutation in RP2 (R120X; 300757.0008) revealed that the expression levels of cofactor C and ARL3 were not affected by the absence of RP2.
Using the highly informative probe M27-beta that detects the DXS255 locus, which is differentially methylated on the active and inactive X chromosomes, Friedrich et al. (1993) determined the methylation status of the RP2 gene in 7 obligate carrier females and 6 daughters of obligate carriers, all from the same family, whose linkage relationships suggested that they carried the RP2 gene. In 5 blind heterozygotes (aged 43 to 68 years), they found that the X chromosome carrying the RP2 gene was methylated and active in nearly all cells. The opposite X-inactivation pattern was found in a carrier female, aged 45 years, who gave normal findings on eye examination. Carriers with less skewed X inactivation had a less severe clinical outcome. However, Friedrich et al. (1993) found little or no correlation between phenotypes and the methylation status of the X chromosomes.
By searching protein sequence databases, Schwahn et al. (2001) determined that RP2 and cofactor C represent members of 2 distinct orthologous groups. All previously identified missense mutations in RP2 affected amino acid residues which are conserved in all RP2 orthologs or both orthologous groups. Studies of RP2-green fluorescent protein fusion proteins in transiently transfected cells showed that a mutation in the N terminus of RP2 abolished localization to the plasma membrane, whereas C-terminal protein truncation mutations led to scattered fluorescent foci in the cytoplasm. Western blot analysis failed to detect RP2 protein in immortalized cell lines from patients with protein truncation mutations, while mRNA was still present. The authors concluded that loss of RP2 protein and/or aberrant intracellular distribution might be the basis for the photoreceptor cell degeneration in most RP2 cases.
Teague et al. (1994) analyzed 40 kindreds with X-linked retinitis pigmentosa for linkage heterogeneity, concluding that 56% were of the RP3 type and 26% of the RP2 type. Bayesian probabilities of linkage to RP2, RP3, or to neither locus were calculated. This showed that 20 of 40 kindreds could be assigned to one or the other locus, with a probability of more than 0.70 (14 RP3 kindreds and 6 RP2 kindreds). A further 3 kindreds were found to be unlinked to either locus, with a probability of more than 0.8. The remaining 17 kindreds could not be classified unambiguously. This highlighted the difficulty of classifying families in the presence of genetic heterogeneity, where the 2 loci are separated by an estimated 16 cM.
Aldred et al. (1994) described RP2 and RP3 regions of Xp. In one case, reassessment of the family in light of these results suggested that the affected individuals may, in fact, have an autosomal dominant form of RP. The remaining 2 families were consistent with X linkage and suggested the possibility of a new X-linked RP locus.
Miano et al. (2001) stated that as many as 5 distinct loci on the X chromosome determine X-linked retinitis pigmentosa, but only 2 XLRP genes had been identified: RPGR (312610) and RP2. Mutations in these genes account for approximately 70% and 10% of XLRP patients, respectively. Clinically, there are no clearly significant differences between RP3 and RP2 phenotypes.
Sharon et al. (2003) screened 187 unrelated male patients for mutations in the RP2 and RPGR genes, including 135 with a prior clinical diagnosis of XLRP, 11 with probable XLRP, 30 isolated cases suspected of having XLRP, and 11 with cone-rod degeneration. Among the 187 patients, they found 10 mutations in RP2, 2 of which were novel, and 80 mutations in RPGR, 41 of which were novel; 66% of the RPGR mutations were within ORF15. Among the 135 with a prior clinical diagnosis of XLRP, mutations in the RP2 and RPGR genes were found in 9 of 135 (6.7%) and 98 of 135 (72.6%), respectively, for a total of 79% of patients. Patients with RP2 mutations had, on average, lower visual acuity but similar visual field area, final dark-adapted threshold, and 30-Hz ERG amplitude compared with those with RPGR mutations.
Pelletier et al. (2007) reported the screening of the RP2 and RPGR genes in a cohort of 127 French families comprising 93 familial cases of retinitis pigmentosa suggesting X-linked inheritance, including 48 of 93 families; 7 male sibships of RP; 25 sporadic male cases of RP; and 2 cone dystrophies (COD). They identified a total of 14 RP2 mutations, 12 of which were novel, in 14 of 88 familial cases of RP and 1 of 25 sporadic male cases (4%). In 13 of 14 of the familial cases, no expression of the disease was noted in females, while in 1 of 14 families 1 woman developed retinitis pigmentosa in the third decade. A total of 42 RPGR mutations, 26 of which were novel, were identified in 80 families, including 69 of 88 familial cases (78.4%); 2 of 7 male sibship cases (28.6%); 8 of 25 sporadic male cases (32%); and 1 of 2 COD. No expression of the disease was noted in females in 41 of 69 familial cases (59.4%), while at least 1 severely affected woman was recognized in 28 of 69 families (40.6%). The frequency of RP2 and RPGR mutations in familial cases of retinitis pigmentosa suggestive of X-linked transmission was in accordance with that reported elsewhere (RP2: 15.9% vs 6-20%; RPGR: 78.4% vs 55-90%). About 30% of male sporadic cases and 30% of male sibships of RP carried RP2 or RPGR mutations, confirming the pertinence of the genetic screening of XLRP genes in male patients affected with RP commencing in the first decade and leading to profound visual impairment before the age of 30 years.
Spence et al. (1974) analyzed a large pedigree in which some heterozygous females had full-blown RP, making it difficult to distinguish X-linked from autosomal dominant inheritance with reduced penetrance. A computerized analysis indicated that the X-linked model is more than 1,000 times more likely than the autosomal model. Gieser et al. (1980) suggested that vitreous fluorophotometry may be a sensitive method for detecting heterozygous females. Grutzner et al. (1972) concluded that the loci for RP, for Xg blood group, and for color vision are widely separated on the X chromosome.
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