Ординатура / Офтальмология / Английские материалы / Retinal Degenerations biology, diagnostics, and therapeutics_Tombran-Tink, Barnstable_2007

verification of rescue experiments once putative modifiers have been identified. With this first success in screening modifiers in mice, one is hopeful that future screens may be employed to identify therapeutic targets in mouse models of human disease.

SUMMARY AND PERSPECTIVES

Recent figures provided on a publicly available website suggest the existence of at least 158 cloned and/or mapped genes that, when mutated, lead to retinal degeneration (80) (Retnet: http://sph.uth.tmc.edu/Retnet/disease.htm). At the present time, modifiers have been reported for only a relatively small percentage of these genes (listed in Tables 1 and 2), although it has been conjectured that most mutations are modified, at least to some extent, on different genetic backgrounds (81). As methods that improve the efficiency of identifying these genetic modifiers are applied, it is hoped that pathways and mechanisms important in function and maintenance of the visual systems will be determined. As more genes modifying the progression of retinal degeneration are discovered, it is envisioned that these modifiers will provide therapeutic targets that are more amenable to treatment than the primary mutant gene, unlocking doors to new treatment modalities.

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common in some Mediterranean and African countries. However, two extremely thorough population-based studies, covering multiple ascertainment sources in populations of more than 1 million, found prevalences for RP in the region of 1 in 1500 people, which is probably the most accurate figure (12,13). In the United States, Fishman found that 16% of his sample of patients with RP showed X-linkage (14) compared with 14–16% in two UK studies (4,15). Assuming therefore that 15% of all RP cases are caused by X-linkage (which compares well with 15–20% estimated from molecular data) then XLRP has a population prevalence of 1 in 9400. Assuming a lower percentage of X-linked cases, such as 10%, then the prevalence of XLRP would be 1 in 15,000. A prevalence study that fails to examine female family members for the carrier state or to account for excess simplex males or male multiplex sibships are likely to underestimate significantly the proportion of all RP caused by X-linked disease.

CLINICAL MANIFESTATIONS OF XLRP

The earliest clinical manifestation of XLRP in males is generally night blindness, with onset in the first decade, progressing to reduction in visual fields in the second decade, a reduction in visual acuity by age 20 and severe visual loss (<20/200) by age 40 (16). More than half of all XLRP hemizygotes (affected males) are symptomatic by age 10 and only 16% retain useful vision by age 40 (15,16). The average age at onset in XLRP has been reported to be 7.2 ± 1.7 yr (17), so that this is one of the most consistently severe forms of RP. Other clinical features have been noted, including some that are seen in all types of RP and others that show at least some predilection for the X-linked subtype. The former include the characteristic bone spicule fundus deposits, attenuation of retinal arterioles, optic disk pallor, posterior subcapsular lens opacities, and absent or subnormal electroretinogram (ERG) amplitudes. The signs that are more indicative of X-linked RP (but by no means diagnostic) include macular or foveal lesions, impaired color vision (blue-yellow defect), and a spherical refractive error of –2.00 diopters or greater (18). However, XLRP cannot be distinguished clinically from other severe forms of retinal dystrophy.

Carrier females in XLRP can show some relatively characteristic features (16,18). The most common manifestations in carriers are however rather non-specific, such as late-onset night blindness, both pigment epithelial changes and a few pigmentary deposits in the peripheral retina, associated with full-field ERG abnormalities, such as reduced amplitude to white light or delayed cone-wave implicit times (16,19,20). The flicker ERG may also be abnormal in XLRP, implicating a reduced signal-to-noise ratio in the rod system compared with normal (21). The signs that show greater specificity for the carrier state include, first, the tapetal reflex, noted by Frost first in 1902 (22) and later described in detail by Falls and Cotterman (23). It is a golden metallic sheen in the macular region, best seen on direct ophthalmoscopy, named after the similar appearance seen in many mammals (but not humans) that have a tapetum lucidum (a reflective layer of the choroid), when a light is shone into the eye at night. However, the sign is only present in a minority of carrier families (16). More recently, Lorenz and co-workers described patchy loss of rod and cone sensitivity in XLRP carriers by two-color threshold perimetry, with rods more severely affected than cones (24). However, a new and more specific finding was an abnormal radial pattern of fundus

autofluorescence in 80% of carriers. The authors suggested that the radial pattern could be explained by random X-inactivation in early embryogenesis and a radial and centrifugal pattern of cell growth in the developing retina (24). If confirmed, this would provide a useful and relatively simple and specific test for the X-linked carrier state. Because XLRP carriers under the age of 40 yr are often asymptomatic and yet are at 1 in 2 risk of having affected sons, this type of test would be useful for genetic counselling. Recognizing XLRP pedigrees is often not straightforward because family sizes are commonly small. Recognizing the carrier state in mothers of single-affected males or male siblings with such a test would help to recognize XLRP and initiate genetic testing.

The key pedigree features that alert the clinician to the possibility of XLRP are a classical X-linked inheritance pattern with affected males and unaffected or more mildly affected but transmitting females and absence of male-to-male transmission. What is often confusing and results in mislabeling of XLRP pedigrees as autosomal dominant ones is the presence of severely affected females in a pedigree in which there is no male-to-male transmission. There has long been debate as to whether X-linked dominant or intermediate compared with recessive inheritance occurs in XLRP and the matter is still not fully resolved. There do appear to be some pedigrees in which female carriers are more consistently or severely affected than others. This probably mirrors the severity of the responsible mutation but chance skewing of X-inactivation and ascertainment bias probably also contribute.

Early genetic linkage studies established the presence of two major XLRP loci (RP3, RP2), situated 16–25 cM apart on the short arm of the X chromosome (25,26). The results indicated that the RP3 locus in Xp21.1 accounted for 60 to 75% of the XLRP families analysed and the remainder mapped to the RP2 locus in the Xp11.2-p11.3 region. This led to prolonged and difficult positional cloning efforts, which finally led, firstly, to the identification of the gene responsible for RP3, the RP GTPase Regulator or RPGR gene (27,28).

RP3 TYPE X-LINKED RP AND THE RPGR GENE

The RPGR gene is located in chromosomal region Xp21.1 and spans 172 kb (29). There are multiple alternatively spliced transcripts, all of which encode an amino

(N)-terminal RCC1-like domain (RLD) that is structurally similar to the RCC1 protein, a guanine nucleotide exchange factor for the small GTP-binding protein, Ran (27,29,30). The X-ray crystallographic structure of RCC1 consists of a seven-bladed propeller formed from internal repeats of 51–68 residues per blade (30). The RLD of RPGR interacts with at least two proteins, RPGRIP1 (31–33) and a 17 kD prenyl binding protein called PDED (34). RPGRIP1 has multiple isoforms that are of unknown function but contains a long N-terminal coiled-coil domain, a Ca2 phospholipid binding domain, and a carboxyl C-terminal RPGR interaction domain (31–33). Mutations in RPGRIP1 were subsequently shown to cause a form of congenital retinal blindness, Leber’s congenital amaurosis, in 5–10% of patients (35,36) and a subtype of cone-rod dystrophy (CRD) (37). The function of the 17 kD prenyl binding protein is also unclear but it binds prenylated photoreceptor proteins such as opsin kinase (GRK1, GRK7), rod cGMP phosphodiesterase (PDE6) subunits, and the small GTPase Rab8 (38). It is