Affinage

RDH5

Retinol dehydrogenase 5 · UniProt Q92781

Length
318 aa
Mass
35.0 kDa
Annotated
2026-04-28
36 papers in source corpus 8 papers cited in narrative 8 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RDH5 is an NADP-dependent 11-cis-retinol dehydrogenase of the short-chain dehydrogenase/reductase (SDR) family that catalyzes the oxidation of 11-cis-retinol and 9-cis-retinol to their corresponding retinaldehydes in the retinal pigment epithelium, constituting the terminal step of visual chromophore regeneration (PMID:9931293, PMID:11418621). Its transcription in RPE is directly regulated by MITF, and loss of RDH5 in knockout mice causes accumulation of cis-retinoid intermediates and progressive structural retinal degeneration with RPE vacuolization (PMID:26876013, PMID:11418621, PMID:32271812). Wild-type RDH5 protein is degraded via autophagy-lysosomes, whereas the fundus albipunctatus-associated L310delinsEV mutant is retained in the endoplasmic reticulum and targeted for proteasomal degradation through AMFR E3 ligase-mediated polyubiquitination at K179 and K263 (PMID:41679585). Loss-of-function mutations in RDH5, including the catalytic-tyrosine variant p.Tyr175Phe, cause the inherited retinal disease fundus albipunctatus (PMID:25820994).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 1999 High

    Characterization of recombinant RDH5 established its substrate repertoire, showing it oxidizes 9-cis-retinol as efficiently as 11-cis-retinol and possesses 3α-hydroxysteroid dehydrogenase activity, defining RDH5 as more than a mono-substrate enzyme.

    Evidence In vitro enzymatic assays with recombinant human RDH5 against multiple retinoid and steroid substrates

    PMID:9931293

    Open questions at the time
    • Physiological relevance of 3α-hydroxysteroid dehydrogenase activity in RPE not established
    • Cofactor preference (NADP vs NAD) not fully defined in this study
    • No in vivo validation of dual substrate utilization
  2. 2001 High

    Rdh5 knockout mice demonstrated that RDH5 is the major 11-cis-retinol dehydrogenase in RPE, as its loss caused accumulation of cis-retinoid intermediates after bleach, while revealing residual NADP-dependent RDH activity with distinct stereospecificity.

    Evidence Rdh5 knockout mouse model with retinoid HPLC quantification and microsomal enzymatic assays

    PMID:11418621

    Open questions at the time
    • Identity of the residual NADP-dependent RDH activity in RPE microsomes not determined
    • Long-term retinal degeneration phenotype not assessed in this initial KO study
    • Compensation mechanisms by other retinol dehydrogenases not characterized
  3. 2015 Medium

    Identification of a p.Tyr175Phe mutation in a fundus albipunctatus patient pinpointed the invariant SDR catalytic tyrosine as essential for RDH5 function, linking a specific catalytic residue to human disease.

    Evidence Direct sequencing of RDH5 in a patient with fundus albipunctatus; bioinformatic mapping to SDR catalytic tetrad

    PMID:25820994

    Open questions at the time
    • No in vitro enzymatic assay of the Y175F mutant protein performed
    • Single family; no independent replication reported
    • Protein stability and folding of Y175F mutant not assessed
  4. 2016 High

    MITF was identified as a direct transcriptional regulator of RDH5 in RPE, establishing the upstream transcription factor controlling chromophore regeneration enzyme expression.

    Evidence Mitf-knockout mouse embryos; siRNA and overexpression of MITF in human RPE cells with RDH5 protein readout; functional rescue with 9-cis-retinal

    PMID:26876013

    Open questions at the time
    • Direct MITF binding to the RDH5 promoter not demonstrated by ChIP
    • Other transcription factors regulating RDH5 in RPE not identified
    • Whether MITF regulation of RDH5 is altered in disease states not explored
  5. 2020 Medium

    Longitudinal analysis of Rdh5−/− mice revealed progressive retinal layer thinning and RPE vacuolization, establishing that RDH5 loss causes structural retinal degeneration beyond the delayed dark adaptation phenotype.

    Evidence SD-OCT longitudinal imaging, histology, and electron microscopy in Rdh5−/− mice

    PMID:32271812

    Open questions at the time
    • Molecular identity of accumulated vacuolar contents not determined
    • Whether degeneration is due to retinoid toxicity, lipofuscin accumulation, or other mechanisms not resolved
    • Time course relationship between retinoid accumulation and structural degeneration not established
  6. 2026 High

    The degradation pathway of disease-associated versus wild-type RDH5 was resolved: wild-type RDH5 undergoes autophagy-lysosomal turnover, whereas the L310delinsEV mutant is retained in the ER and degraded by AMFR-mediated polyubiquitination at K179 and K263 via the proteasome, explaining accelerated mutant protein loss.

    Evidence Co-IP of RDH5 with AMFR; siRNA/overexpression of AMFR; K179R/K263R mutagenesis; proteasome and lysosome inhibitor treatments; half-life assays

    PMID:41679585

    Open questions at the time
    • Whether other disease-causing RDH5 mutations are similarly degraded via AMFR/proteasome not tested
    • Whether pharmacological proteasome inhibition can rescue mutant RDH5 function in vivo not assessed
    • Structural basis for AMFR recognition of the L310delinsEV mutant not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis for RDH5 substrate selectivity, the identity of compensatory retinol dehydrogenases in RPE, and the therapeutic tractability of stabilizing disease-causing RDH5 mutants remain unresolved.
  • No crystal structure or cryo-EM structure of human RDH5 available
  • Identity of residual NADP-dependent 11-cis-RDH in RPE still unknown
  • Whether pharmacological chaperones or proteasome inhibitors can rescue mutant RDH5 enzymatic activity in vivo not tested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016491 oxidoreductase activity 2
Localization
GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-9709957 Sensory Perception 3 R-HSA-1430728 Metabolism 2
Partners
AMFRMITF

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 Recombinant human RDH5 (11-cis-retinol dehydrogenase) catalyzes 9-cis-retinol metabolism equally efficiently as 11-cis-retinol metabolism, and also exhibits 3α-hydroxysteroid dehydrogenase activity recognizing 5α-androstan-3α,17β-diol and androsterone as substrates, but lacks 17β-hydroxysteroid and 11β-hydroxysteroid dehydrogenase activities. In vitro enzymatic assay with recombinant human RDH5 protein The Biochemical Journal High 9931293
2001 RDH5 encodes the major 11-cis-retinol dehydrogenase responsible for oxidizing 11-cis-retinol to 11-cis-retinal in the retinal pigment epithelium (RPE); knockout of Rdh5 in mice leads to accumulation of cis-retinoids (particularly 13-cis-isomers) after bleach, and remaining RPE microsomal RDH activity shows NADP-dependent specificity toward 9-cis- and 11-cis-retinal but not 13-cis-retinal. Rdh5 knockout mouse model; retinoid HPLC analysis; microsomal enzymatic activity assays with cofactor specificity testing The Journal of Biological Chemistry High 11418621
2016 MITF (microphthalmia-associated transcription factor) directly regulates transcription of Rdh5 in the RPE; Mitf-deficient mouse embryos show downregulation of Rdh5 and Rlbp1, and experimental manipulation of MITF levels in human RPE cells leads to corresponding changes in RDH5 protein levels. Mitf-knockout mouse embryo analysis; siRNA/overexpression in human RPE cells; rescue with 9-cis-retinal supplementation Scientific Reports High 26876013
2015 A missense mutation p.Tyr175Phe in RDH5 affecting the invariant catalytic tyrosine of the short-chain alcohol dehydrogenase/reductase (SDR) family causes fundus albipunctatus, establishing Tyr175 as essential for RDH5 enzymatic activity. Direct sequencing of RDH5 in a patient with fundus albipunctatus; bioinformatic analysis of SDR conserved residues Journal of Applied Genetics Medium 25820994
2026 The disease-associated RDH5/L310delinsEV mutant protein has a shortened half-life compared to wild-type RDH5; unlike wild-type RDH5 (which is degraded via autophagy-lysosomes), the mutant is retained in the endoplasmic reticulum and undergoes polyubiquitination by the E3 ligase AMFR at lysine residues K179 and K263, leading to proteasomal degradation. K179R/K263R double mutation reduces AMFR-mediated ubiquitination and degradation. Co-immunoprecipitation of RDH5 with AMFR; siRNA knockdown and overexpression of AMFR; half-life assay; site-directed mutagenesis (K179R, K263R); proteasome inhibitor treatment; lysosome inhibitor treatment Experimental Eye Research High 41679585
2023 In ARPE-19 cells, RDH5 knockdown by siRNA significantly upregulates MMP-2 and TGF-β2 mRNA, and all-trans retinoic acid (ATRA) suppresses RDH5 expression while promoting MMP-2 and TGF-β2 expression, suggesting RDH5 is involved in ATRA-mediated epithelial-mesenchymal transition regulation in RPE cells. siRNA knockdown of RDH5 in ARPE-19 cells; qRT-PCR for MMP-2 and TGF-β2; ATRA dose-response treatment International Journal of Ophthalmology Low 37332553
2025 CRISPR/Cas9-mediated knockdown of rdh5 in zebrafish phenocopies behavioral defects seen in chd7 mutants (CHARGE syndrome model), identifying rdh5 as a downstream target of Chd7 that mediates specific CHARGE-related behavioral phenotypes. CRISPR/Cas9 knockdown in zebrafish; transcriptomic/proteomic integration; behavioral phenotyping bioRxivpreprint Low bio_10.1101_2025.07.28.666396
2020 Rdh5−/− mice show progressive thinning of inner and outer retinal layers measurable by SD-OCT, with intracellular accumulation of low-density vacuoles in the RPE detected by electron microscopy, demonstrating that RDH5 loss causes structural retinal degeneration beyond functional delay. Longitudinal SD-OCT of Rdh5−/− mice; histology; electron microscopy PLoS One Medium 32271812

Source papers

Stage 0 corpus · 36 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 A high association with cone dystrophy in Fundus albipunctatus caused by mutations of the RDH5 gene. Investigative ophthalmology & visual science 87 11053295
2007 Altered vitamin A homeostasis and increased size and adiposity in the rdh1-null mouse. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 77 17435174
1999 Activity of human 11-cis-retinol dehydrogenase (Rdh5) with steroids and retinoids and expression of its mRNA in extra-ocular human tissue. The Biochemical journal 74 9931293
2011 Phenotypic variability in RDH5 retinopathy (Fundus Albipunctatus). Ophthalmology 72 21529959
2001 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. The Journal of biological chemistry 60 11418621
2005 Cone and rod dysfunction in fundus albipunctatus with RDH5 mutation: an electrophysiological study. Investigative ophthalmology & visual science 42 15790919
2003 RDH5 gene mutations and electroretinogram in fundus albipunctatus with or without macular dystrophy: RDH5 mutations and ERG in fundus albipunctatus. Documenta ophthalmologica. Advances in ophthalmology 36 12906118
2013 Cone abnormalities in fundus albipunctatus associated with RDH5 mutations assessed using adaptive optics scanning laser ophthalmoscopy. American journal of ophthalmology 35 24246574
2000 A frequent 1085delC/insGAAG mutation in the RDH5 gene in Japanese patients with fundus albipunctatus. Investigative ophthalmology & visual science 34 10845614
2016 Microphthalmia-associated transcription factor regulates the visual cycle genes Rlbp1 and Rdh5 in the retinal pigment epithelium. Scientific reports 33 26876013
2012 Multimodal fundus imaging in fundus albipunctatus with RDH5 mutation: a newly identified compound heterozygous mutation and review of the literature. Documenta ophthalmologica. Advances in ophthalmology 32 22669287
2001 A novel Gly35Ser mutation in the RDH5 gene in a Japanese family with fundus albipunctatus associated with cone dystrophy. Archives of ophthalmology (Chicago, Ill. : 1960) 32 11448328
2020 RDH5-Related Fundus Albipunctatus in a Large Japanese Cohort. Investigative ophthalmology & visual science 30 32232344
2003 A novel RDH5 gene mutation in a patient with fundus albipunctatus presenting with macular atrophy and fading white dots. American journal of ophthalmology 26 12967826
2015 Fundus albipunctatus: review of the literature and report of a novel RDH5 gene mutation affecting the invariant tyrosine (p.Tyr175Phe). Journal of applied genetics 22 25820994
2019 RDH1 suppresses adiposity by promoting brown adipose adaptation to fasting and re-feeding. Cellular and molecular life sciences : CMLS 21 30788515
2007 Fundus albipunctatus in a 6-year old girl due to compound heterozygous mutations in the RDH5 gene. Documenta ophthalmologica. Advances in ophthalmology 21 17476461
2000 A novel compound heterozygous mutation in the RDH5 gene in a patient with fundus albipunctatus. American journal of ophthalmology 20 11078852
2012 Novel mutations in RDH5 cause fundus albipunctatus in two consanguineous Pakistani families. Molecular vision 17 22736946
2022 A large animal model of RDH5-associated retinopathy recapitulates important features of the human phenotype. Human molecular genetics 15 34726233
2008 Novel RDH5 mutation in family with mother having fundus albipunctatus and three children with retinitis pigmentosa. Ophthalmic genetics 14 18363170
2006 Compound heterozygous RDH5 mutations in familial fleck retina with night blindness. Acta ophthalmologica Scandinavica 14 16637847
2004 A novel homozygous Gly107Arg mutation in the RDH5 gene in a Japanese patient with fundus albipunctatus with sectorial retinitis pigmentosa. Ophthalmic research 14 15007239
2015 RDH5 retinopathy (fundus albipunctatus) with preserved rod function. Retina (Philadelphia, Pa.) 11 25170858
2022 THE TARGET SIGN: A Near Infrared Feature and Multimodal Imaging in a Pluri-Ethnic Cohort with RDH5-Related Fundus Albipunctatus. Retina (Philadelphia, Pa.) 9 35250012
2024 RDH5 and RLBP1-Associated Inherited Retinal Diseases: Refining the Spectrum of Stationary and Progressive Phenotypes. American journal of ophthalmology 7 38945349
2023 All-trans retinoic acid regulates the expression of MMP-2 and TGF-β2 via RDH5 in retinal pigment epithelium cells. International journal of ophthalmology 6 37332553
2020 A spectral-domain optical coherence tomographic analysis of Rdh5-/- mice retina. PloS one 5 32271812
2018 A novel mutation in RDH5 gene causes retinitis pigmentosa in consanguineous Pakistani family. Genes & genomics 4 29892959
2022 A Novel Pathogenic Variant in the RDH5 Gene in a Patient with Fundus Albipunctatus and Severe Macular Atrophy. Case reports in genetics 3 35433063
2003 Gene structure and minimal promoter of mouse rdh1. Gene 3 12594048
2023 Selection signature analysis reveals RDH5 performed key function in vision during sheep domestication process. Archives animal breeding 2 37384328
2022 Novel variants in the RDH5 Gene in a Chinese Han family with fundus albipunctatus. BMC ophthalmology 2 35148716
2026 Fundus albipunctatus disease-associated RDH5/L310delinsEV mutation undertakes AMFR-mediated polyubiquitination and degradation in proteasome. Experimental eye research 0 41679585
2021 [Fundus albipunctatus with mutations in the RDH5 gene (clinical case)]. Vestnik oftalmologii 0 33610152
2020 A founder RDH5 splice site mutation leads to retinitis punctata albescens in two inbred Pakistani kindreds. Ophthalmic genetics 0 31933420