Ocular albinism type 1 (OAl, OMIM: 300500) is an X-linked disorder characterised by severe impairment o f visual acuity, retinal hypopigmentation, nystagmus and the presence o f macromelanosomes. The gene, mapped to a critical region in Xp22.3-22.2, was cloned in
1995 by Bassl et al. and was found to be expressed at high levels in RNA samples from retina, including the retinal pigment epithelium. The 424 amino acid protein encoded by the
O A l gene displays several putative transmembrane domains and shares no similarities with previously identified molecules. Schiaffino et al. (1999) provided structural evidence that the protein product o f the O Al gene, a pigment cell-specific integral membrane glycoprotein, represents a novel member of the G protein-coupled receptors (GPCR) superfamily and demonstrated that it binds heterotrimeric G proteins. Incerti et al. (2000) generated and characterised OAl-deficient mice by gene targeting. Ophthalmologic examination showed hypopigmentation o f the ocular fundus in mutant animals compared with wild type.
-Retinoschisis
Retinoschisis (RS, OMIM: 312700) is described as intraretinal splitting due to retinal degeneration. Affected males show cystic degeneration leading to split in the retina, detachment of the retina, and finally complete retinal atrophy with sclerosis o f the choroid (George et al. 1996). Impairment o f vision is slowly progressive. The typical lesions displayed in RS patients are thought to be related to a defect in retinal Muller cells. Sauer et al. (1997), suggested that as Muller cells have been shown to aid neurite outgrowth and neuronal connections, failure to establish a proper neuronal interaction may be the indirect result o f a Muller-cell defect. Consequently, it has been suggested that RS may be considered a disorder o f retinal development rather than a dystrophic process. The X L R Sl gene, cloned by Sauer et al. in 1997, was found to be exclusively expressed in the retina. The predicted protein sequence, named retinoschisin, was found to contain a highly conserved motif implicated in cell-cell interaction and thus may be active in cell adhesion processes during retinal development. Grayson et al. (2000) suggested that retinoschisin is released by photoreceptors and has functions within the inner retinal layers, therefore X-linked retinoschisis may be caused by abnormalities in a putative secreted photoreceptor protein.
-Norrie disease
Norrie disease (NDP, OMIM: 310600) is an X-linked neurological disorder characterised by congenital blindness due to bilateral retina dysplasia showing abnormal vascularisation o f the peripheral retina, mental disturbances and progressive sensorineural
deafness in one-third of the patients (Warburg 1966). Using a positional cloning strategy the
NDP (or norrin) gene was isolated in 1992 by two different groups (Berger et al. and Chen et al.) and was found to be exclusively expressed in retina, brain and choroid. Mutations in the same gene were also found to cause familial X-linked exudative retinopathy (FEVRX, Chen
et al. 1993), a disorder characterised by retinal traction, peripheral vitreous opacities, and subretinal and intraretinal exudates (OMIM: 305390) and retinopathy o f prematurity (ROP, Shastry et al. 1997) a retinal vascular disease occurring in infants with short gestational age and low birth weight, which can lead to retinal detachment. Protein sequence comparisons revealed homologies with cysteine-rich protein-binding domains o f proteins implicated in the regulation o f cell proliferation (Chen et al. 1993), suggesting that the NDP protein likewise may be involved in the pathway that regulates neural cell differentiation and proliferation. To elucidate the cellular and molecular processes involved in Norrie disease, Berger et al.
(1996) used gene targeting technology to generate NDP mutant mice. Hemizygous mice carrying a replacement mutation in exon 2 o f the NDP gene developed retrolental structures in the vitreous body and showed an overall disorganisation of the retinal ganglion cell layer with loss of photoreceptor outer segments.
-Aland Island Eye Disease
Aland island eye disease (AIED, OMIM: 300600) is a disorder described in a family from the Aland Islands in the Sea o f Bothnia, characterised by albinism o f the fundus, hypoplasia o f the fovea, visual impairment, nystagmus, myopia, astigmatism, and colour vision abnormalities. Initially the phenotype o f this family suggested that AIED was a variant o f ocular albinism (O A l) and was given the locus symbol 0A 2. Subsequently Weleber et al.
(1989) pointed out that electroretinography examinations (ERGs) in AIED patients showed many differences between this disorder and O A l, whilst similarities were found with CSNB; they thus suggested the possibility that AIED should be classified as a type o f CSNB. Since the gene responsible for AIED has been assigned to the DXS7-DXS225 interval in X p ll.3 (Alitalo et al. 1991, Glass et al. 1993) allelism between AIED and one o f the two CSNB loci, both located in the pericentromeric region o f the short arm o f the X chromosome, remains open.
-Choroideremia
Choroideremia (CHM, OMIM: 303100) is an X-linked condition whose clinical symptoms include progressive loss o f vision, characterised by reduction o f central vision, constriction o f visual fields and night blindness, beginning at an early age, and the complete atrophy o f choroid and retina. By linkage analysis the disease gene was located to the X ql3- q21 interval by Schwartz et al. (1986). With the aid o f four different deletions found in males affected by choroideremia Cremers et al. (1990) isolated a 45 kb genomic DNA segment corresponding to this region of deletion overlap. Conserved sequences from this DNA segment were used as a probe to screen a human retinal cDNA library and a transcript expressed in choroid, retinal pigment epithelium and other cells was detected. Isolation and characterisation o f the complete open reading frame o f the CHM gene and its exon-intron structure was later reported by van Bokhoven et al. (1994). A gene targeting approach was used by van den Hurk et al. (1997) to disrupt the mouse gene, which was shown to be lethal in male embryos, and in females embryos only if the mutation is of maternal origin, giving evidence o f an X-linked imprinted gene. In both heterozygous females and chimeras, the mutation caused photoreceptor cell degeneration. Consequently, conditional rescue o f the embryonic lethal phenotype o f the ohm mutation may provide a faithful mouse model for choroideremia.
-Optic Atrophy
Optic atrophy (OMIM: 165500) is a disorder characterised by decreased visual acuity, colour vision deficits, and optic nerve pallor. Went et al. (1975) described a family with a very early onset of the disease, perhaps present at birth and with a very slow progression o f the loss o f visual acuity. Genetic analysis o f this family (Assink et al. 1997) placed the gene in the Xpl 1.4-pl 1.21 interval between markers DXS993 and DXS991 (0PA2, OMIM: 311050).
-Red and Green cone pigments
Red and green cone pigments {RCP and GCP) are responsible for protanopia (red, or protan, colourblindness, PCB) and deuteranopia (green, or deutan, colour-blindness, DCP) respectively (OMIM: 303900 and 303800). Red and green opsins are bound to the
chromophore 11-cw retinal to form the visual pigment in cone photoreceptor cells and have different absorption spectra. Colour-blindness arises from alterations in one o f the genes encoding one o f the cone opsins. In western Europeans, about 8% o f males are colour-blind. O f these, about 75 % have a defect in the deutan (green) series and about 25% have a defect in the protan (red) series. The genes coding each o f the two visual pigments situated on Xq28, and the blue pigment situated on chromosome 7, were isolated by Nathans et al.
(1986).