RDH12 (Retinol dehydrogenase 12) — review notes

UniProt: Q96NR8 (RDH12_HUMAN). Gene: RDH12 (synonym SDR7C2). Human, 316 aa.
Source of truth used here: genes/human/RDH12/RDH12-uniprot.txt, genes/human/RDH12/RDH12-goa.tsv,
cached publications, and cached Reactome entries.

Summary of biology

RDH12 is a member of the short-chain dehydrogenase/reductase (SDR) superfamily
(SDR family 7C member 2). It is a microsomal (endoplasmic reticulum membrane)
retinoid dehydrogenase/reductase expressed most notably in the retina, where the
protein localizes to photoreceptor inner segments.

• Enzymology: strong preference for NADP(H) over NAD(H); reduces
  9-cis-, 11-cis- and all-trans-retinaldehyde to the corresponding retinols, and
  (with lower affinity) reduces medium-chain lipid-peroxidation aldehydes such as
  4-hydroxynonenal (4-HNE) and trans-2-nonenal. EC 1.1.1.300.
• Physiological direction: in cells the enzyme "primarily contributes to the
  reduction of all-trans-retinaldehyde" (i.e. retinaldehyde -> retinol), and in
  photoreceptors under oxidative stress it also detoxifies lipid-peroxidation
  aldehydes.
• Disease: biallelic RDH12 variants cause Leber congenital amaurosis 13 (LCA13)
  and autosomal-recessive retinitis pigmentosa 53 (RP53); most pathogenic
  missense variants cause profound loss of catalytic activity.

Key provenance (verbatim quotes)

Enzymatic function / substrate specificity

• [file:human/RDH12/RDH12-uniprot.txt "Retinoids dehydrogenase/reductase with a clear preference for"] and the
  continuation "NADP. Displays high activity towards 9-cis, 11-cis and all-trans-" retinal
  (UniProt FUNCTION comment; lines wrapped with CC prefix so not a single grep-able span).
• [file:human/RDH12/RDH12-uniprot.txt "EC=1.1.1.300"] with the catalytic-activity Rhea reaction
  "all-trans-retinol + NADP(+) = all-trans-retinal + NADPH".
• PMID:12226107 — establishes RDH12 as an SDR retinol dehydrogenase.
• PMID:12226107 — dual (all-trans/cis) substrate specificity; source of the IDA MF annotations.
• PMID:15865448 — NADP(H) preference (basis for treating the NAD+ term as over-annotation).
• PMID:15865448 — all-trans-retinal is the best substrate.
• PMID:15865448 — physiological reductive direction (retinaldehyde -> retinol).

Aldehyde detoxification (BP: cellular detoxification of aldehyde)

• PMID:19686838 — IDA support for GO:0110095.
• PMID:19686838 — inner-segment localization of activity.
• PMID:15865448.

Localization

• [file:human/RDH12/RDH12-uniprot.txt "Endoplasmic reticulum membrane"] (SUBCELLULAR LOCATION, ECO:0000269|PubMed:15865448) — EXP support for GO:0005789.
• PMID:19686838 — photoreceptor inner segment localization (mouse ortholog basis for the ISS/IEA human annotations).

Visual cycle role (indirect/auxiliary)

• PMID:19686838 — RDH12's role in vision is auxiliary; supports KEEP_AS_NON_CORE for "visual perception".
• PMID:12226107 — proposed (not proven) visual-cycle role.

Disease

• [file:human/RDH12/RDH12-uniprot.txt "Leber congenital amaurosis 13 (LCA13)"] and
  [file:human/RDH12/RDH12-uniprot.txt "Retinitis pigmentosa 53 (RP53)"] — DISEASE comments (ECO:0000269 experimental variant references).
• Reactome R-HSA-2466861 "Defective RDH12 does not reduce atRAL to atROL" links loss-of-function variants (Y226C, H151N, A126V etc.) to LCA13/RP53.

Protein-binding (IPI) annotations

Four GO:0005515 "protein binding" IPI annotations come from high-throughput
interactome/degradation studies with no RDH12-specific functional interpretation:
- PMID:20006610 (RDH12 disease-variant degradation; with UBC / ubiquitin, EBI IntAct)
- PMID:25416956 (proteome-scale interactome map; with RBPMS)
- PMID:25910212 (interaction perturbations in genetic disorders; with RBPMS-3)
- PMID:32296183 (HuRI reference binary interactome; with PLEKHA7)
These are uninformative for the molecular function (bare "protein binding") and are
marked as over-annotations rather than removed (experimental IPI). UniProt records the
same partners (PLEKHA7, RBPMS, UBC) in its INTERACTION section.

Curation decisions (high level)

• Core MF: GO:0052650 all-trans-retinol dehydrogenase (NADP+) activity and
  GO:0102354 11-cis-retinol dehydrogenase (NADP+) activity (EXP/IDA), plus
  GO:0050661 NADP binding (cofactor, from KM data / NADP-binding motif).
• Core BP: GO:0110095 cellular detoxification of aldehyde (IDA) and
  GO:0042572 retinol metabolic process / retinoid metabolism.
• Core CC: GO:0005789 endoplasmic reticulum membrane (EXP) and
  GO:0001917 photoreceptor inner segment.
• GO:0008106 "alcohol dehydrogenase (NADP+) activity" (IEA/Rhea) is a correct but
  overly general parent — MODIFY to the specific retinol-dehydrogenase terms.
• GO:0004745 "all-trans-retinol dehydrogenase (NAD+) activity" — the NAD+-dependent
  version is a laboratory-detectable but physiologically minor activity (KM for NAD(H)
  ~2000-fold higher than NADP(H)); marked as over-annotation, not core.
• "visual perception" (GO:0007601) and "photoreceptor cell maintenance" (GO:0045494)
  are retained as non-core because RDH12's contribution to the visual cycle is indirect.