Autosomal recessive childhood-onset severe retinal dystrophy (arCSRD) designates a heterogeneous group of disorders affecting rod and cone photoreceptors simultaneously. The most severe cases are termed Leber congenital amaurosis (LCA), while the less aggressive forms are usually considered juvenile retinitis pigmentosa. Recently, mutations in the retinal-specific guanylate cyclase gene were found in patients with LCA. Disease genes implicated in other forms of arCSRD are expected to encode proteins present in the neuroretina or in the retinal pigment epithelium (RPE). The RPE, a monolayer of cells separating the vascular-rich choroid and the neuroretina, is in intimate contact with the outer segments of rods and cones via the microvilli surrounding the photoreceptors. The RPE expresses a tissue-specific and evolutionarily highly conserved 61 kD protein (RPE65) present at high levels in vivo. Although the function of RPE65 is not yet known, an important role in the RPE/photoreceptor vitamin-A cycle is suggested by the fact that RPE65 associates both with serum retinol-binding protein and with the RPE-specific 11-cis retinol dehydrogenase, an enzyme active in the synthesis of the visual pigment chromophore 11-cis retinal. Here we report that the analysis of RPE65 in a collection of about 100 unselected retinal-dystrophy patients of different ethnic origin revealed five that are likely to be pathogenic mutations, including a missense mutation (Pro363Thr), two point mutations affecting splicing (912 + 1G-->T and 65 + 5G-->A) and two small re-arrangements (ins144T and 831del8) on a total of nine alleles of five patients with arCSRD. In contrast to other genes whose defects have been implicated in degenerative retinopathies, RPE65 is the first disease gene in this group of inherited disorders that is expressed exclusively in the RPE, and may play a role in vitamin-A metabolism of the retina.
The disks of vertebrate photoreceptors are produced by outgrowths of the plasma membrane. Hence genes that encode retinal proteins targeted to plasma membrane protrusions represent candidates for inherited retinal degenerations. One such candidate is the gene encoding human prominin (mouse)-like 1 (PROML1, previously known as AC133 antigen) which belongs to the prominin family of 5-transmembrane domain proteins. Murine prominin (prom) shows a strong preference for plasma membrane protrusions in a variety of epithelial cells whereas PROML1 is expressed in retinoblastoma cell lines and adult retina. In the present study, molecular genetic analyses of a pedigree segregating for autosomal recessive retinal degeneration indicated that the affected individuals were homozygous for a nucleotide 1878 deletion in PROML1. This alteration is predicted to result in a frameshift at codon 614 with premature termination of translation. Expression of a similar prom deletion mutant in CHO cells indicated that the truncated protein does not reach the cell surface. Immunocytochemistry revealed that prom is concentrated in the plasma membrane evaginations at the base of the outer segments of rod photoreceptors. These findings suggest that loss of prominin causes retinal degeneration, possibly because of impaired generation of the evaginations and/or impaired conversion of the evaginations to disks.
Inadequate levels of all-trans-retinol in the blood cause retinal dysfunction; hence, genes implicated in retinal vitamin-A metabolism represent candidates for inherited retinal degenerations. In the current study, molecular genetic analysis of a consanguineous pedigree segregating for non-syndromic autosomal recessive retinitis pigmentosa (arRP) indicated that the affected siblings were homozygous by descent for a G4763A nucleotide substitution in RLBP1, the gene encoding cellular retinaldehyde-binding protein (CRALBP). This substitution is predicted to replace an arginine with glutamine at residue 150. CRALBP is not expressed in photoreceptors but is abundant in the retinal pigment epithelium (RPE) and Müller cells of the neuroretina, where it carries 11-cis-retinol and 11-cis-retinaldehyde. When expressed in bacteria, recombinant CRALBP (rCRALBP) containing the R150Q substitution was less soluble than wild-type rCRALBP. Mutant rCRALBP was purified from the soluble cell lysate and the protein structure was verified by mass spectrometry. The mutant protein lacked the ability to bind 11-cis-retinaldehyde. These findings suggest that arRP in the current pedigree results from a lack of functional CRALBP, presumably leading to disruption of retinal vitamin-A metabolism.
The 5-year results of the COBEST demonstrated that the CS has an enduring patency advantage over the BMS in both the short and long terms. Furthermore, the CS showed acceptable patency rates for the treatment of more severe TASC C and D lesions, and patients who received a CS required fewer revascularization procedures. However, the choice of stent did not affect the rate of major limb amputations.
Multilocus linkage analysis of 62 family pedigrees with X chromosome-linked retinitis pigmentosa (XLRP) was undertaken to determine the presence of possible multiple disease loci and to reliably estimate their map location. Multilocus homogeneity tests furnished convincing evidence for the presence of two XLRP loci, the likelihood ratio being 6.4 x 109:1 in favor of two versus a single XLRP locus and gave accurate estimates for their map location. In 60-75% of the families, location of an XLRP gene was estimated at 1 centimorgan distal to OTC, and in 25-40% ofthe families, an XLRP locus was located halfway between DXS14 (p58-1) and DXZJ (Xcen), with an estimated recombination fraction of 25% between the two XLRP loci. There is also good evidence for a third XLRP locus, midway between DXS28 (C7) and DXS164 (pERT87), supported by a likelihood ratio of 293:1 for three versus two XLRP loci.Retinitis pigmentosa (RP) is a group of hereditary progressive disorders of the retina characterized initially by night blindness, often within the first two decades of life, reduction of peripheral or side vision, eventual decrease in central vision to variable degrees, in many cases leading to total blindness due to degeneration of the retina (1). There are several subtypes of RP, including autosomal recessive, autosomal dominant, and X chromosome-linked forms (XLRP).Linkage analyses in families with XLRP have shown conflicting results regarding the location of the disease locus. Consequently, the presence of two XLRP loci was hypothesized (2-5). One subtype of XLRP, referred to as RP2, was linked to locus DXS7 (L1.28) (6, 7); another subtype, RP3, was linked to locus OTC (ornithine carbamoyltransferase) (8-10). Further evidence for location of an XLRP locus distal to OTC came from a patient with a deletion starting between OTC and DXS84 (754) and extending toward the telomere, in whom several X-chromosome linked diseases occurred including RP (11). Friedrich et al. (12) found another locus responsible for XLRP to be closely linked to DXS7, between Xcen and DXS7 (L1.28).The current study was initiated as a collaborative effort (i) to obtain evidence for XLRP heterogeneity if at all present, and, if so, (ii) to localize the disease loci in a comprehensive linkage and heterogeneity analysis.Family Data. A total of 62 families were available for this analysis, most but not all of which have been published previously. For calculation efficiency, some pedigrees had earlier been broken down into smaller families and analyzed separately; here, they were analyzed undivided. Disease status for both affected males and carrier females was determined by the investigators and was incorporated unaltered in this analysis.In many cases, heterozygous women also have symptoms that are, however, generally much milder than in men. Where detectable, such symptoms have been used for carrier status determination.Linkage Analysis. The linkage analysis was carried out with the LINKAGE programs version 4.7 (13). Map distances between markers whos...
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