X-linked retinitis pigmentosa (XLRP) is a severe form of inherited retinal degeneration that primarily affects the rod photoreceptors (Demirci et al., 2002). It typically causes an early-onset night blindness and loss of peripheral vision, often causing patients to ... X-linked retinitis pigmentosa (XLRP) is a severe form of inherited retinal degeneration that primarily affects the rod photoreceptors (Demirci et al., 2002). It typically causes an early-onset night blindness and loss of peripheral vision, often causing patients to become legally blind by the age of 30 to 40 years. In RP3, affected males have a severe phenotype, and carrier females show a wide spectrum of clinical features ranging from completely asymptomatic to severe RP (Jin et al., 2007). Mutation in the RPGR gene is believed to account for approximately 70% of XLRP (Vervoort et al., 2000).
Falls and Cotterman (1948) described an X-linked form of choroidoretinal degeneration which is distinguished from other types by the presence in heterozygous women of a tapetal-like retinal reflex (a brilliant, scintillating, golden-hued, patchy appearance most striking around the ... Falls and Cotterman (1948) described an X-linked form of choroidoretinal degeneration which is distinguished from other types by the presence in heterozygous women of a tapetal-like retinal reflex (a brilliant, scintillating, golden-hued, patchy appearance most striking around the macula) but no visual defect. Curtis and Blank (1989) studied a family in which a carrier female had an unusual tapetal reflex, the macula having 'a beaten metal appearance, with glistening patches.' The data supported the conclusion that retinitis pigmentosa with tapetal reflex is a separate entity. Keith et al. (1991) described a large Australian family with extreme clinical variability in the hemizygotes: 1 member had typical rod-cone disease, 3 had the cone-rod pattern, and 1 had macroscopic changes in the macular area only, but showed low potentials in the ERG. From a study of reported case histories, Keith et al. (1991) concluded that clinical variability is a common feature of X-linked retinitis pigmentosa. McGuire et al. (1995) studied 31 members of a 5-generation American family that included 7 affected females and 5 affected males. All 5 affected males showed diffuse retinal atrophy with round pigment cobblestone clumps, optic atrophy pallor with temporal loss, and myopia. Three young males when first tested at age 7 months and 11 years had nonrecordable electroretinograms and severely constricted visual fields. Six of the 7 affected females were evaluated several times over a period of 14 years. Five of these 6 had electroretinograms ranging from unrecordable to 80% of normal in the cone isolated ERG and ranging from nonrecordable to 45% of normal in the rod isolated ERG. Two affected females had moderately abnormal electroretinograms, which became nonrecordable and barely recordable after 14 years. In these 2 individuals, diffuse retinal atrophy was present with fine to granular pigment in equatorial regions. Mild nonprogressive myopia was present. McGuire et al. (1995) found that the clinical phenotype in the XLRP family studied by them was consistent with X-linked dominance, with expression milder and more variable in females. Souied et al. (1997) described 9 families that showed an X-linked pattern of inheritance with a total of 28 affected males and 34 affected females. The females in these families met criteria for the diagnosis of retinitis pigmentosa. The males had a delayed onset of disease, with central vision being preserved until 40 to 45 years of age. Linkage to the RP3 locus was demonstrated, but SSCP and sequence analysis of the RPGR gene demonstrated no mutations. Four of the 9 families were later shown to have mutations at the RP3 locus (Rozet et al., 2002). Grover et al. (2000) evaluated the progression of visual impairment in carriers of XLRP. They described the relationship between retinal findings at presentation and the extent of subsequent deterioration. They followed visual acuity, visual field, and electroretinograms 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 about their visual prognosis. Demirci et al. (2002) noted that affected males in the RP15 family studied by McGuire et al. (1995) and Mears et al. (2000) were reported to have early cone involvement, and the diagnosis of one of the patients from the series of Vervoort et al. (2000) was 'probable' X-linked cone dystrophy. Demirci et al. (2002) suggested that these patients may represent intermediate phenotypes within the broad spectrum of retinal disease caused by RPGR mutations. 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 due to mutations in the RPGR gene (312610) and the other of patients with autosomal dominant RP due to mutations in the RHO gene (see 180380). 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. Loss of acuity in RPGR patients appeared to be associated with foveal thinning.
Meindl et al. (1996) provided evidence that loss-of-function mutations within the RPGR gene (312610) are responsible for RP3 by identifying 2 small intragenic deletions and 2 nonsense and 3 missense mutations in highly conserved residues in unrelated patients ... Meindl et al. (1996) provided evidence that loss-of-function mutations within the RPGR gene (312610) are responsible for RP3 by identifying 2 small intragenic deletions and 2 nonsense and 3 missense mutations in highly conserved residues in unrelated patients with X-linked RP. In an affected member of the family reported by McGuire et al. (1995), Mears et al. (2000) detected a de novo insertion in exon ORF15 of the RPGR gene (312610.0013); this exon had been identified by Vervoort et al. (2000), who found it to be a mutation hotspot. The identification of an RPGR mutation in a family with a severe form of cone-rod degeneration suggested that RPGR mutations may encompass a broader phenotypic spectrum than had previously been recognized in 'typical' retinitis pigmentosa. In 4 of the 9 families with XLRP reported by Souied et al. (1997), Rozet et al. (2002) identified mutations in exon ORF15 of the RPGR gene. Rozet et al. (2002) also reported 5 additional affected families with mutations in ORF15. All 7 of the identified mutations were predicted to result in a truncated protein. Rozet et al. (2002) noted that the age at onset in affected females was delayed compared to affected males (20 to 40 years vs 10 to 20 years, respectively). Demirci et al. (2006) reported a 16-year-old boy with RP and bilateral Coats-like vasculopathy (see 300216) in whom they identified a mutation in the RPGR gene (312610.0024). The mutation segregated with RP in the family, but clinical findings in other family members, including 2 affected male patients and 3 obligate carrier females, were consistent with typical X-linked recessive RP. Because the proband was the only family member who had Coats-like RP, Demirci et al. (2006) suggested that other genetic and/or environmental factors might be involved. In affected individuals from an Israeli family with 'semi-dominant' X-linked retinitis pigmentosa, in which obligatory female carriers manifested high myopia, low visual acuity, constricted visual fields, and severely reduced electroretinogram amplitudes, Banin et al. (2007) identified a mutation in the RPGR gene (G275S; 312610.0003). The authors stated that obligate carriers from 2 unrelated Danish families in which Roepman et al. (1996) previously identified this mutation had no visual complaints and normal to slightly reduced retinal function. The disease-related RPGR haplotype of the Israeli family was found to be different from that of the 2 Danish families, indicating that the G275R mutation arose twice independently on different X-chromosome backgrounds. Genetic analysis excluded skewed X-inactivation patterns, chromosomal abnormalities, distorted RPGR expression levels, and mutations in 3 candidate genes as the cause for the differences in disease severity of female carriers. Banin et al. (2007) suggested that an additional gene or genes linked to RPGR modulate disease expression in severely affected carriers. Branham et al. (2012) screened 214 male patients with simplex retinal degenerative disease, 185 with RP and 29 with cone/cone-rod dystrophy (COD/CORD), for mutations in the RPGR and RP2 genes. They identified pathogenic mutations in 32 (15%) of the patients. Four patients with COD/CORD had a mutation in the ORF15 mutation hotspot of the RPGR gene. Of the RP patients, 3 had mutations in RP2 and 25 had mutations in RPGR (including 23 in the ORF15 region). Branham et al. (2012) concluded that their results demonstrated a substantial contribution of RPGR mutations to retinal degenerations, and in particular to simplex RP. They suggested that RPGR should be considered as a first tier gene for screening isolated males with retinal degeneration. Nishiguchi et al. (2013) identified a Japanese male patient with retinitis pigmentosa who was heterozygous for a frameshift mutation in the ciliary gene NEK2 (604043.0001), but who also carried a frameshift mutation in the known RP-associated RPGR gene (312610.0026) that had previously been described as a sufficient cause of X-linked RP by Vervoort et al. (2000); studies in zebrafish suggested that the RPGR allele interacts in trans with the NEK2 locus to exacerbate photoreceptor defects.
Buraczynska et al. (1997) stated that RP3 is the most frequent genetic subtype of X-linked retinitis pigmentosa.
Vervoort et al. (2000) found RPGR mutations in 72% of XLRP patients, of which 20% were in exons 1 ... Buraczynska et al. (1997) stated that RP3 is the most frequent genetic subtype of X-linked retinitis pigmentosa. Vervoort et al. (2000) found RPGR mutations in 72% of XLRP patients, of which 20% were in exons 1 through 14 and 80% were in the repetitive purine-rich sequence of exon ORF15. This suggested that at least 11% of all RP referrals may be accounted for by this locus. Bader et al. (2003) screened 58 German XLRP families and found RP2 (300757) mutations in 8% and RPGR mutations in 71%, thus confirming the high frequency of the RP3 subtype.