Disease relevance of RDH5

• 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 [1].
• 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 [1].
• Microarray and reverse transcriptase-PCR analyses revealed reduced expression of two retinoid biosynthesis genes: retinol dehydrogenase 5 (RDH5) and retinol dehydrogenase L (RDHL) in colon adenomas and carcinomas as compared with normal colon [2].
• Consistent with the adenoma and carcinomas samples, seven colon carcinoma cell lines also lacked expression of RDH5 and RDHL [2].
• PURPOSE: To identify the frequency of a mutation of the RDH5 gene in Japanese patients with hereditary retinal degeneration and to characterize clinical findings for the patients associated with a 1085delC/insGAAG mutation in the RDH5 gene [3].

High impact information on RDH5

• 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 [1].
• Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus [1].
• 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 [4].
• We identified Rdh5 as a retina-specific retinol dehydrogenase controlled by APC [5].
• Morpholino knockdown of Rdh5 phenocopied the apc mutant retinal differentiation defects and was rescued by treatment with exogenous all-trans retinoic acid [5].

Chemical compound and disease context of RDH5

• Characterization of a dehydrogenase activity responsible for oxidation of 11-cis-retinol in the retinal pigment epithelium of mice with a disrupted RDH5 gene. A model for the human hereditary disease fundus albipunctatus [6].

Biological context of RDH5

• The disease phenotype was only manifested in family members with two abnormal RDH5 alleles consistent with autosomal recessive inheritance in both pedigrees [7].
• CONCLUSION: A novel compound heterozygous missense mutation in the RDH5 gene was found in a patient with fundus albipunctatus [8].
• METHOD: We examined the RDH5 gene genotype in members of a Japanese family [8].
• Genomic DNA was extracted from leukocytes of the peripheral blood, and exons 2, 3, 4, and 5 of the RDH5 gene were amplified by polymerase chain reaction and were directly sequenced [9].
• Considered along with the identical nucleotide sequences in the untranslated regions of human Rdh5 and human 9-cis-retinol dehydrogenase cDNAs and the nearly identical nucleotide sequences overall (99% identity), the current results suggest that the two cDNAs represent a single gene product [10].

Anatomical context of RDH5

• The prototypic enzyme RDH5 and the related enzyme CRAD1 have been shown to face the lumen of the endoplasmic reticulum (ER), suggesting a compartmentalized synthesis of retinal [11].
• Rdh5 mRNA expression was widespread in extra-ocular tissues with human liver (100% relative expression in extra-ocular tissues only) and mammary gland (97% relative to liver) showing the most intense signals [10].
• Human fetal tissues also expressed Rdh5 with fetal liver showing the most intense expression among the fetal tissues (20%) [10].
• Pathways in addition to 11-cis-RDH likely provide 11-cis-retinal for rods and cones and can maintain normal kinetics of visual recovery but only under certain constraints and less efficiently for cone than rod function [12].

Associations of RDH5 with chemical compounds

• Altered kinetic parameters were observed for RDH5 oxidation of 11-cis-retinol bound to rCRALBP mutants M222A, M225A, and W244F, supporting impaired substrate carrier function [13].
• Generation of double and triple knockouts will aid in determining if these retinol dehydrogenases are responsible for the remaining 11-cis-retinol oxidation observed in RDH5 knockout animals [14].
• PATIENTS: We studied the ocular findings in 6 members of a Japanese family with fundus albipunctatus with cone dystrophy and a guanine-to-adenine transversion at the first nucleotide in codon 35 of the RDH5 gene [15].
• The mutation resulted in a substitution of serine for glycine in amino acid 35 (Gly35Ser) of the RDH5 gene [15].
• Protein structures were verified by amino acid analysis and mass spectrometry, retinoid binding properties were evaluated by UV-visible and fluorescence spectroscopy and substrate carrier functions were assayed for recombinant 11-cis-retinol dehydrogenase (rRDH5) [16].

Regulatory relationships of RDH5

• 11-cis-RDH is expressed in the RPE and not in the neural retina [12].

Other interactions of RDH5

• The diagnosis was determined clinically and RBP3 and RDH5 were analyzed by molecular screening methods and direct genomic sequencing [7].
• RPA is associated mostly with mutations in RLBP1 and occasionally in RHO, RDS, and RDH5 [17].
• CONCLUSIONS: We suggest that the macular dystrophy is caused by the RDH5 gene mutation as a phenotype variation in fundus albipunctatus [18].
• Interaction of 11-cis-retinol dehydrogenase with the chromophore of retinal g protein-coupled receptor opsin [19].

Analytical, diagnostic and therapeutic context of RDH5

• In this report, an animal model for this disease, 11-cis-rdh-/- mice, was used to investigate the flow of retinoids after a bleach, and microsomal membranes from the retinal pigment epithelium of these mice were employed to characterize remaining enzymatic activities oxidizing 11-cis-retinol [6].

References