RDH12 (retinol dehydrogenase 12; SDR family 7C member 2) is a NADPH-dependent retinaldehyde reductase / retinol dehydrogenase of the short-chain dehydrogenase/reductase (SDR) superfamily. It is an endoplasmic reticulum (microsomal) membrane enzyme, expressed most notably in the retina where it localizes to photoreceptor inner segments. With a strong preference for NADP(H) over NAD(H), it reduces all-trans-, 9-cis- and 11-cis-retinaldehyde to the corresponding retinols (EC 1.1.1.300), and, with lower affinity, reduces medium-chain lipid-peroxidation aldehydes such as 4-hydroxynonenal and trans-2-nonenal. In photoreceptors its principal physiological role is to reduce all-trans-retinaldehyde (contributing an auxiliary, inner-segment step complementary to outer-segment retinol dehydrogenases in the visual cycle) and to detoxify reactive lipid-peroxidation aldehydes generated during light-induced oxidative stress, thereby protecting photoreceptors from apoptosis. Biallelic loss-of-function variants in RDH12 cause Leber congenital amaurosis type 13 (LCA13) and autosomal-recessive retinitis pigmentosa (RP53).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Correct subcellular location. RDH12 is a microsomal ER-membrane enzyme; this UniProtKB-SubCell mapping is directly corroborated by the experimental annotation from PMID:15865448. |
| GO:0008106 alcohol dehydrogenase (NADP+) activity | IEA GO_REF:0000116 | MODIFY | Summary: Chemically correct but overly general parent term derived from Rhea reactions. The specific, experimentally supported activities are the retinol/retinaldehyde dehydrogenase terms; modify to the specific substrate-level function. Proposed replacements: all-trans-retinol dehydrogenase (NADP+) activity Supporting Evidence: file:human/RDH12/RDH12-uniprot.txt Retinoids dehydrogenase/reductase with a clear preference for |
| GO:0052650 all-trans-retinol dehydrogenase (NADP+) activity | IEA GO_REF:0000120 | ACCEPT | Summary: Core molecular function. The NADP(H)-dependent all-trans-retinol / all-trans-retinaldehyde interconversion (EC 1.1.1.300) is the best-characterized activity of RDH12 and is directly supported by experimental annotations (EXP/IDA) below. Supporting Evidence: file:human/RDH12/RDH12-uniprot.txt EC=1.1.1.300 |
| GO:0102354 11-cis-retinol dehydrogenase (NADP+) activity | IEA GO_REF:0000116 | ACCEPT | Summary: Correct. RDH12 displays high NADP(H)-dependent activity toward 11-cis-retinal/retinol; also supported by the experimental (EXP) annotations below. |
| GO:0005515 protein binding | IPI PMID:20006610 Disease-associated variants of microsomal retinol dehydrogen... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" (IPI) from an interaction detected in a disease-variant degradation study (partner UBC/ubiquitin per GOA WITH/FROM). Uninformative about molecular function; retained as an over-annotation rather than removed (experimental IPI). |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" (IPI) from a proteome-scale interactome map (partner RBPMS). High-throughput two-hybrid interaction with no RDH12-specific functional interpretation; uninformative for molecular function. |
| GO:0005515 protein binding | IPI PMID:25910212 Widespread macromolecular interaction perturbations in human... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" (IPI) from a large-scale interactome-perturbation study (partner RBPMS isoform). Uninformative for molecular function. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" (IPI) from the HuRI reference binary interactome (partner PLEKHA7). High-throughput screen; uninformative for molecular function and marked as an over-annotation. |
| GO:0001917 photoreceptor inner segment | IEA GO_REF:0000107 | ACCEPT | Summary: Correct localization transferred from the mouse ortholog. RDH12 is a photoreceptor inner-segment protein, consistent with immunolocalization in PMID:19686838 and the ISS annotation below. |
| GO:0004745 all-trans-retinol dehydrogenase (NAD+) activity | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: RDH12 has a ~2000-fold higher Km for NAD(H) than for NADP(H), so the NAD+-dependent activity is a laboratory-detectable but physiologically minor activity; NADP(H) is the strongly preferred cofactor. Marked as an over-annotation. Supporting Evidence: PMID:15865448 RDH12 exhibits approximately 2000-fold lower K(m) values for NADP(+) and NADPH than for NAD(+) and NADH |
| GO:0007601 visual perception | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: RDH12 contributes to vision, but its role in the visual cycle is indirect (inner-segment auxiliary reduction; knockout mice retain normal chromophore synthesis). Retained as a non-core process annotation. Supporting Evidence: PMID:19686838 their contribution to visual cycle activity per se is likely to be indirect |
| GO:0042572 retinol metabolic process | IEA GO_REF:0000120 | ACCEPT | Summary: Correct. RDH12 participates in retinol metabolism via NADPH-dependent retinaldehyde reduction; also supported by the experimental (IDA) annotation from PMID:12226107 below. |
| GO:0110095 cellular detoxification of aldehyde | IEA GO_REF:0000107 | ACCEPT | Summary: Correct process. RDH12 reduces the lipid-peroxidation aldehyde 4-hydroxynonenal to a nontoxic alcohol in photoreceptors; directly supported by the IDA annotation from PMID:19686838 below. |
| GO:0001523 retinoid metabolic process | TAS Reactome:R-HSA-2453902 | ACCEPT | Summary: Correct. RDH12 acts in the retinoid (visual) cycle, reducing retinaldehyde to retinol. Accurate general process annotation from Reactome. |
| GO:0052650 all-trans-retinol dehydrogenase (NADP+) activity | TAS Reactome:R-HSA-2464822 | ACCEPT | Summary: Core molecular function, consistent with the experimental annotations. Reactome models RDH12 reducing all-trans-retinal to all-trans-retinol. |
| GO:0052650 all-trans-retinol dehydrogenase (NADP+) activity | TAS Reactome:R-HSA-2466861 | ACCEPT | Summary: Core molecular function from the Reactome "defective RDH12" (LCA13/RP53) reaction; the wild-type activity is the NADP(H)-dependent atRAL->atROL reduction. |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:15865448 Biochemical properties of purified human retinol dehydrogena... | ACCEPT | Summary: Experimentally supported core localization: purified/characterized human RDH12 is an endoplasmic reticulum (microsomal) membrane enzyme. Supporting Evidence: file:human/RDH12/RDH12-uniprot.txt Endoplasmic reticulum membrane |
| GO:0052650 all-trans-retinol dehydrogenase (NADP+) activity | EXP PMID:15865448 Biochemical properties of purified human retinol dehydrogena... | ACCEPT | Summary: Core molecular function with direct experimental support. Purified human RDH12 recognizes retinoids as substrates with a clear NADP(H) preference; all-trans-retinal is the most efficient substrate. Supporting Evidence: PMID:15865448 The enzyme exhibits the highest catalytic efficiency for all-trans-retinal |
| GO:0102354 11-cis-retinol dehydrogenase (NADP+) activity | EXP PMID:12226107 Dual-substrate specificity short chain retinol dehydrogenase... | ACCEPT | Summary: Core molecular function. RDH12 was identified as a dual-substrate SDR that metabolizes both all-trans- and cis-retinols, including the 11-cis form. Supporting Evidence: PMID:12226107 four retinol dehydrogenases (RDH11-14) that display dual-substrate specificity, uniquely metabolizing all-trans- and cis-retinols |
| GO:0102354 11-cis-retinol dehydrogenase (NADP+) activity | EXP PMID:15865448 Biochemical properties of purified human retinol dehydrogena... | ACCEPT | Summary: Core molecular function with experimental support; purified RDH12 shows NADP(H)-dependent 11-cis-retinal/retinol activity. |
| GO:0060342 photoreceptor inner segment membrane | TAS Reactome:R-HSA-2466861 | ACCEPT | Summary: Consistent with the ER-membrane / inner-segment localization of RDH12. Reactome places the reaction at the photoreceptor inner segment membrane. |
| GO:0007601 visual perception | IMP PMID:12226107 Dual-substrate specificity short chain retinol dehydrogenase... | KEEP AS NON CORE | Summary: RDH12's contribution to vision is genuine but indirect/auxiliary (its loss does not limit chromophore synthesis in knockout mice). Retained as a non-core process rather than a core function; not removed (experimental IMP annotation). Supporting Evidence: PMID:12226107 photoreceptor RDH12 could be involved in the production of 11-cis-retinal from 11-cis-retinol during regeneration of the cone visual pigments |
| GO:0110095 cellular detoxification of aldehyde | IDA PMID:19686838 Retinol dehydrogenase 12 detoxifies 4-hydroxynonenal in phot... | ACCEPT | Summary: Core biological process with direct experimental support. In mouse retina RDH12 reduces the lipid-peroxidation product 4-HNE to a nontoxic alcohol, protecting photoreceptors from light-induced oxidative damage. Supporting Evidence: PMID:19686838 in mouse retina RDH12 reduces 4-HNE to a nontoxic alcohol, protecting cellular macromolecules against oxidative modification and protecting photoreceptors from light-induced apoptosis |
| GO:0052650 all-trans-retinol dehydrogenase (NADP+) activity | IDA PMID:12226107 Dual-substrate specificity short chain retinol dehydrogenase... | ACCEPT | Summary: Core molecular function with direct experimental support. RDH12 catalyzes the NADP(H)-dependent all-trans-retinol/retinaldehyde interconversion. Supporting Evidence: PMID:12226107 catalyze the transformation of retinol to |
| GO:0001917 photoreceptor inner segment | ISS GO_REF:0000024 | ACCEPT | Summary: Correct core localization inferred from the mouse ortholog and supported by immunolocalization; RDH12 resides in photoreceptor inner segments. Supporting Evidence: PMID:19686838 a microsomal retinoid dehydrogenase/reductase (RDH) located in photoreceptor inner segments |
| GO:0060342 photoreceptor inner segment membrane | TAS Reactome:R-HSA-2464822 | ACCEPT | Summary: Consistent with RDH12's ER-membrane / photoreceptor inner-segment localization. Duplicate of the other Reactome inner-segment-membrane annotation. |
| GO:0004745 all-trans-retinol dehydrogenase (NAD+) activity | IDA PMID:12226107 Dual-substrate specificity short chain retinol dehydrogenase... | MARK AS OVER ANNOTATED | Summary: NAD+-dependent activity is measurable in vitro but physiologically minor: RDH12 has a clear NADP(H) preference (Km for NAD(H) ~2000-fold higher). Marked as over-annotation rather than a core function; not removed (experimental IDA). Supporting Evidence: PMID:15865448 RDH12 exhibits approximately 2000-fold lower K(m) values for NADP(+) and NADPH than for NAD(+) and NADH |
| GO:0007601 visual perception | TAS PMID:12226107 Dual-substrate specificity short chain retinol dehydrogenase... | KEEP AS NON CORE | Summary: RDH12 contributes to vision indirectly via the retinoid cycle; retained as a non-core process (its enzymatic reduction of retinaldehyde is the core function that underlies this role). |
| GO:0042572 retinol metabolic process | IDA PMID:12226107 Dual-substrate specificity short chain retinol dehydrogenase... | ACCEPT | Summary: Core biological process with direct experimental support: RDH12 participates in retinol metabolism through NADP(H)-dependent retinol/retinaldehyde interconversion. Supporting Evidence: PMID:12226107 catalyze the transformation of retinol to |
| GO:0045494 photoreceptor cell maintenance | TAS PMID:12226107 Dual-substrate specificity short chain retinol dehydrogenase... | KEEP AS NON CORE | Summary: Plausible downstream/pleiotropic role: RDH12 loss causes progressive photoreceptor degeneration (LCA13/RP53), consistent with a maintenance role, but this is a disease-inferred consequence of losing the core enzymatic activity rather than a core function itself. Retained as non-core. |
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