Bothnia dystrophy caused by mutations in the cellular retinaldehyde-binding protein gene (RLBP1) on chromosome 15q26.
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PURPOSE: To determine the chromosomal location and to identify the gene causing a type of retinitis punctata albescens, called Bothnia dystrophy, found in a restricted geographic area in northern Sweden. METHODS: Twenty patients from seven families originating from a restricted geographic area in northern Sweden were clinically examined. Microsatellite markers were analyzed in all affected and unaffected family members. Direct genomic sequencing of the gene encoding cellular retinaldehyde-binding protein was performed after the linkage analysis had been completed. RESULTS: Affected individuals showed night blindness from early childhood with features consistent with retinitis punctata albescens and macular degeneration. The responsible gene was mapped to 15q26, the same region to which the cellular retinaldehyde-binding protein gene has been assigned. Subsequent analysis showed all affected patients were homozygous for a C to T substitution in exon 7 of the same gene, leading to the missense mutation Arg234Trp. Analysis of marker haplotypes suggested that all cases had a common ancestor who carried the mutation. CONCLUSIONS: A missense mutation in the cellular retinaldehyde-binding protein gene is the cause of Bothnia dystrophy. The disease is a local variant of retinitis punctata albescens that is common in northern Sweden due to a founder mutation. (+info)
Recessive mutations in the RLBP1 gene encoding cellular retinaldehyde-binding protein in a form of retinitis punctata albescens.
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PURPOSE: To determine the frequency and spectrum of mutations in the RLBP1 gene encoding cellular retinaldehyde-binding protein (CRALBP) in patients with hereditary retinal degeneration. METHODS: The single-strand conformation polymorphism (SSCP) technique and a direct genomic sequencing technique were used to screen the coding exons of this gene (exons 2-8) for mutations in 324 unrelated patients with recessive or isolate retinitis pigmentosa, retinitis punctata albescens, Leber congenital amaurosis, or a related disease. Variant DNA fragments revealed by SSCP analysis were subsequently sequenced. Selected alleles that altered the coding region or intron splice sites were evaluated further through segregation analysis in the families of the index cases. RESULTS: Four novel mutations were identified in this gene among three unrelated patients with recessively inherited retinitis punctata albescens. Two of the mutations were missense: one was a frameshift, and one affected a canonical splice donor site. CONCLUSIONS: Recessive mutations in the RLBP1 gene are an uncommon cause of retinal degeneration in humans. The phenotype produced by RLBP1 mutations seems to be a form of retinitis punctata albescens. (+info)
Phenotypic variations in a family with retinal dystrophy as result of different mutations in the ABCR gene.
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AIMS: To describe two phenotypic variations of autosomal recessive retinal dystrophy occurring in a consanguineous family in a pseudodominant pattern, resulting from mutations in the ATP binding cassette transporter (ABCR) gene. METHODS: Patients of this family underwent an extensive ophthalmic evaluation, including fundus photography, fluorescein angiography, and electroretinography (ERG). Genetic analysis comprised sequence analysis of the retina specific ABCR gene. RESULTS: Five patients presented with decreased visual acuity in the second decade, central chorioretinal atrophy associated with a central scotoma, and severely decreased photopic and scotopic ERG responses. This clinical picture, which in our opinion resembles a cone-rod dystrophy (CRD), was associated with compound heterozygosity for IVS30+ 1g -->t and IVS40+5g-->a mutations in the ABCR gene. The four remaining patients presented with night blindness in the first decade because of a retinitis pigmentosa-like (RP-like) dystrophy. In addition to a pale "waxy" optic disc, attenuated retinal vessels and bone spicule deposits, a widespread chorioretinal atrophy was observed. The scotopic ERG was extinguished and the photopic ERG was severely diminished. Genetic analysis revealed a homozygous 5' splice mutation IVS30+1g -->t in the ABCR gene. CONCLUSION: Mutations in the ABCR gene can cause clinical pictures resembling autosomal recessive RP and autosomal recessive CRD. (+info)
Complete congenital stationary night blindness maps on Xp11.4 in a Sardinian family.
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X-linked congenital stationary night blindness (CSNBX) is a hereditary non-progressive retinal disorder, which can appear in two different clinical forms, complete and incomplete, associated with CSNB1 and CSNB2 loci on Xp. We describe a Sardinian family with complete CSNBX and define better the limits of the CSNB1 genetic locus on Xp11.4 through linkage analysis. Haplotype analysis showed two key recombinants, which restrict the CSNB1 locus to a region of about 3 cM limited by markers DSX1068 and DSX6810 respectively. The locus that we describe is included in the CSNB1 locus defined by previous reports referring to the same clinical form of the disease. These results, in addition to other recent mapping reports about families from different geographical areas, confirm the genetic homogeneity of X-linked complete CSNB. (+info)
Difference between RP2 and RP3 phenotypes in X linked retinitis pigmentosa.
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AIM: X linked retinitis pigmentosa (XLRP) has two genetic loci known as "RP2" and "RP3". Clinical features reported to differentiate RP2 from RP3 include a higher prevalence of myopia and primary cone dysfunction in RP2, and late onset night blindness and tapetal reflex in RP3. Members from 14 XLRP families were examined in an attempt to verify these differences. METHODS: 16 affected males and 37 females from 14 XLRP families assigned as either RP2 or RP3 by haplotype analysis and/or by heterogeneity analysis were examined. Members of all 14 families who were willing to participate but unavailable for examination were contacted and detailed interviews carried out. RESULTS: No clear phenotypic differences were found that could be used to reliably differentiate RP2 from RP3 with respect to myopia and onset of night blindness. The tapetal reflex was also found to be present in carriers of both RP2 and RP3. CONCLUSIONS: XLRP is a heterogeneous class of rod degenerative disorders with no clear phenotypic differentiation between the two genetic loci RP2 and RP3. There is a continuum of clinical presentations which can be seen in both RP2 and RP3, but the features within a given family tend to be consistent. However, interfamilial variability is prevalent leading to a wide range of clinical presentations and more than one abnormal allele at each gene locus cannot be excluded. (+info)
Localization of the mouse nob (no b-wave) gene to the centromeric region of the X chromosome.
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PURPOSE: To determine the position on the X chromosome of the gene responsible for a spontaneous mouse mutation, nob (no b-wave), which matches the phenotype of complete X-linked congenital stationary night blindness (CSNB) type 1 in human. METHODS: Inter- and intraspecific pedigrees were generated, and the phenotype of each mouse was scored on the basis of either the presence or the absence of an electroretinographic b-wave. DNA was isolated from a tail biopsy from each mouse and was used to determine the genotype at various polymorphic markers on the X chromosome. LOD scores (Z) between the nob phenotype and each marker were calculated to determine the most probable location of the nob gene. RESULTS: A total of 174 informative offspring were analyzed. The nob gene is tightly linked to DXMit103 with a maximum LOD score of 25.9 at a recombination fraction of zero. This marker is located at 4.2 cM on the X chromosome of the mouse map. Haplotype analyses of several recombinant chromosomes in the region indicates that the nob gene maps between DXMit54 (3.8 cM) and Ube1x (5.7 cM). CONCLUSIONS: The genetic position of the mouse nob gene overlaps the homologous region in human that contains the locus for CSNB1 and excludes the region of CSNB2. Further studies are planned to identify the mouse nob gene and to evaluate it as a candidate for CSNB1. (+info)
Blue-on-yellow perimetry in the complete type of congenital stationary night blindness.
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PURPOSE: To resolve the discrepancy between nonrecordable full-field short wavelength cone electroretinograms (S-cone ERGs) and the presence of normal color vision in patients with the complete type of congenital stationary night blindness (CSNB1). METHODS: Conventional white-on-white (W-W) perimetry, blue-on-yellow (B-Y) perimetry, and the Farnsworth-Munsell 100-hue test were performed in five patients with CSNB1. Diagnosis of CSNB1 was made by clinical and electrophysiological examinations. Twelve normal, age-matched control subjects and an additional 7 normal, highly myopic subjects were tested. RESULTS: Color vision was normal in all the CSNB1 patients by the Farnsworth-Munsell 100-hue test. B-Y perimetry demonstrated that blue cone sensitivity in CSNB1 was normal in the fixation area, but the mean sensitivities of the entire 60 degrees field, the central 0 degrees-to-15 degrees, and 15 degrees-to-30 degrees ring were significantly decreased compared with the normal and myopic subjects. The sensitivity difference between 15 degrees-to-30 degrees and 0 degrees-to-15 degrees in B-Y perimetry increased significantly in CSNB1 compared with both normal and myopic control subjects. CONCLUSIONS: Our perimetric results demonstrated that the S-cone function in CSNB1 is preserved only in the fovea and becomes abnormal toward the peripheral retina. This accounts for the normal color vision that tests mainly foveal function and the nonrecordable S-cone ERGs that arise mainly from peripheral retina. (+info)
Increased susceptibility to light damage in an arrestin knockout mouse model of Oguchi disease (stationary night blindness)
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PURPOSE: To determine whether constitutive signal flow arising from defective rhodopsin shut-off causes photoreceptor cell death in arrestin knockout mice. METHODS: The retinas of cyclic-light-reared, pigmented arrestin knockout mice and wild-type littermate control mice were examined histologically for photoreceptor cell loss from 100 days to 1 year of age. In separate experiments, to determine whether constant light would accelerate the degeneration in arrestin knockout mice, these animals and wild-type control mice were exposed for 1, 2, or 3 weeks to fluorescent light at an intensity of 115 to 150 fc. The degree of photoreceptor cell loss was quantified histologically by obtaining a mean outer nuclear layer thickness for each animal. RESULTS: In arrestin knockout mice maintained in cyclic light, photoreceptor loss was evident at 100 days of age, and it became progressively more severe, with less than 50% of photoreceptors surviving at 1 year of age. The photoreceptor degeneration appeared to be caused by light, because when these mice were reared in the dark, the retinal structure was indistinguishable from normal. When exposed to constant light, the retinas of wild-type pigmented mice showed no light-induced damage, regardless of exposure duration. By contrast, the retinas of arrestin knockout mice showed rapid degeneration in constant light, with a loss of 30% of photoreceptors after 1 week of exposure and greater than 60% after 3 weeks of exposure. CONCLUSIONS: The results indicate that constitutive signal flow due to arrestin knockout leads to photoreceptor degeneration. Excessive light accelerates the cell death process in pigmented arrestin knockout mice. Human patients with naturally occurring mutations that lead to nonfunctional arrestin and rhodopsin kinase have Oguchi disease, a form of stationary night blindness. The present findings suggest that such patients may be at greater risk of the damaging effects of light than those with other forms of retinal degeneration, and they provide an impetus to restrict excessive light exposure as a protective measure in patients with constitutive signal flow in phototransduction. (+info)