Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus

Abstract

The metabolic pathways that produce 11-cis retinal are important for vision because this retinoid is the chromophore residing in rhodopsin and the cone opsins. The all-trans retinal that is generated after cone and rod photopigments absorb photons of light is recycled back to 11-cis retinal by the retinal pigment epithelium and Müller cells of the retina. Several of the enzymes involved have recently been purified and molecularly cloned; here we focus on 11-cis retinol dehydrogenase (encoded by the gene RDH5; chromosome 12q13-14; ref. 4), the first cloned enzyme in this pathway. This microsomal enzyme is abundant in the retinal pigment epithelium, where it has been proposed to catalyse the conversion of 11-cis retinol to 11-cis retinal. We evaluated patients with hereditary retinal diseases featuring subretinal spots (retinitis punctata albescens and fundus albipunctatus) and patients with typical dominant or recessive retinitis pigmentosa for mutations in RDH5. Mutations were found only in two unrelated patients, both with fundus albipunctatus; they segregated with disease in the respective families. Recombinant mutant 11-cis retinol dehydrogenases had reduced activity compared with recombinant enzyme with wild-type sequence. Our results suggest that mutant alleles in RDH5 are a cause of fundus albipunctatus, a rare form of stationary night blindness characterized by a delay in the regeneration of cone and rod photopigments.

Dual-substrate Specificity Short Chain Retinol Dehydrogenases from the Vertebrate Retina

“…However, disabling mutations in men and mice produce no embryonic developmental abnormalities (16)(17)(18)(19). In this report, we provide unequivocal evidence that RDH11-14 display high activity toward 9-cis-and all-trans-retinol.…”

“…However, the disruption of this gene in a mouse model led to uninterrupted production of 11-cis-retinal (16,17) and a lack of any embryonic abnormalities. Furthermore, patients with fundus albipunctatus who also have a disabling mutation in the RDH5 gene still show efficient production of the chromophore, albeit with slower kinetics (18,19). Here, we characterized members of a novel subfamily of SDRs cloned from the retina that display novel properties of dual cis-and all-trans-retinol substrate specificities.…”

Extreme hyperopia is the result of null mutations inMFRP, which encodes a Frizzled-related protein

“…The moderate and differing delays in dark adaptation observed in the two patients examined (Fig. 3G) could reflect secondary deficiencies in the regeneration of 11-cis retinal (33) or availability of vitamin A (34).…”

Aberrant Metabolites in Mouse Models of Congenital Blinding Diseases: Formation and Storage of Retinyl Esters

“…It has been recently reported that RPE65 possesses retinol isomerase activity (23-26), while RDH5 is one of the enzymes catalyzing the last step of the retinoid cycle, oxidation of 11-cis-retinol to 11-cis-retinal (11,12,17,39). In mice, disruption of the Rdh5 gene results in the accumulation of cis-retinyl esters (15).…”

“…Although RDH5 is responsible for the majority of 11-cis-RDH activity, RDH11 and other RDHs also have a measurable role in regenerating the visual pigment by complementing RDH5 in RPE cells (11). Disruption of the gene encoding RDH5 causes fundus albipunctatus in humans (12,13). Fundus albipunctatus is an autosomal recessive form of congenital stationary night blindness characterized by the appearance of numerous small white dots located in the RPE, a delayed course of dark adaptation, and † This research was supported by NIH Grant EY09339.…”