id: A0A9L0SKW1 gene_symbol: OLFML2A product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9796 label: Equus caballus description: OLFML2A (olfactomedin-like protein 2A, photomedin-1) is a member of the olfactomedin-domain glycoprotein family, in the OLFML2A subfamily of the olfactomedin-related proteins. It has an N-terminal region carrying tandem CXCXCX9C cysteine motifs, a central coiled-coil and disordered segment, and a C-terminal olfactomedin domain. In mammals the canonical product has an N-terminal signal peptide. In the mouse it is secreted as a disulfide-linked, O-glycosylated homodimer, cleaved in the middle of the molecule after secretion, and it binds the sulfated glycosaminoglycans chondroitin sulfate E and heparin. Photomedin-1 is found in the outer segments of retinal photoreceptors and in the major processes of kidney podocytes. Its physiological role beyond glycosaminoglycan binding is not known. The horse locus encodes a signal-peptide-bearing product that is nearly identical in length to the human protein. This UniProt entry (599 residues) is one of several shorter alternative models of the gene. It lacks the signal peptide and a 22-residue N-terminal segment, but it keeps the complete olfactomedin domain. existing_annotations: - term: id: GO:0005576 label: extracellular region evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in supporting_entities: - UniProtKB-SubCell:SL-0243 review: action: ACCEPT summary: OLFML2A is a secreted extracellular protein. The horse locus encodes a leader-bearing form, although this particular leaderless model would not be secreted on its own. reason: 'At the gene level the extracellular location is well grounded. (1) A0A9L0SKW1 belongs to PANTHER subfamily PTHR23192:SF29 (OLFACTOMEDIN-LIKE PROTEIN 2A), with experimentally characterized mouse photomedin-1 (Q8BHP7). That protein is secreted as a disulfide-bonded dimer and is proteolytically processed after secretion (PMID:15836428). (2) PAINT places extracellular region at the family root node PTN000573635. All SF29 members descend from that node, and human OLFML2A carries the corresponding IBA. (3) The earlier review left this row UNDECIDED pending a check of the horse transcript models. That check is now done. The same Ensembl gene (ENSECAG00000023908) has a RefSeq isoform, XP_023484611.2 (650 aa), which carries a hydrophobic leader homologous to the human 1-27 signal peptide and pairs with human over all but five positions. A0A9L0SKW1 is one of several leaderless alternative models of the locus, comparable to human isoform 2, which lacks residues 1-39. On its own sequence it has no secretion signal, and the UniProt mapping behind this row is an ARBA family rule rather than a sequence feature. GO describes the gene product, though, and the gene product is secreted. The row is accepted, and the identity caveat is recorded in the notes.' supported_by: - reference_id: PMID:15836428 supporting_text: These proteins, named photomedin-1 and photomedin-2, were secreted as disulphide-bonded dimers (photomedin-1) or oligomers/multimers (photomedin-2) with O-linked carbohydrate chains, although photomedin-1 was proteolytically processed in the middle of the molecule after secretion. - reference_id: file:HORSE/OLFML2A/OLFML2A-bioinformatics/RESULTS-rereview.md supporting_text: The horse locus encodes a leader-bearing product. - reference_id: file:HORSE/OLFML2A/OLFML2A-bioinformatics/RESULTS-rereview.md supporting_text: The benchmark accession A0A9L0SKW1 is one of several leaderless alternative models of the same gene. - reference_id: file:HORSE/OLFML2A/OLFML2A-uniprot.txt record_section: ["DR:PANTHER"] supporting_text: DR PANTHER; PTHR23192:SF29; OLFACTOMEDIN-LIKE PROTEIN 2A; 1. - reference_id: file:human/OLFML2A/OLFML2A-uniprot.txt record_section: ["FT:SIGNAL"] supporting_text: FT SIGNAL 1..27 - term: id: GO:0050840 label: extracellular matrix binding evidence_type: ISS original_reference_id: PMID:15836428 review: action: NEW summary: Binding of sulfated glycosaminoglycans, transferred within the OLFML2A subfamily from mouse photomedin-1. reason: Mouse photomedin-1 (Q8BHP7) carries an IDA annotation for this term from PMID:15836428. In a panel of ECM components it bound chondroitin sulfate E and heparin preferentially. The horse protein is a PANTHER SF29 ortholog of the mouse protein, and its olfactomedin domain is intact, including the cysteines of the conserved intradomain disulfide. Only the mouse protein has been assayed, and the binding site has not been mapped, so the transfer is made at the level of the mouse IDA term. More specific heparin-binding or chondroitin-sulfate-binding terms are not used. This is the only molecular activity established for the subfamily. It is not evidence that the protein organizes the matrix. supported_by: - reference_id: PMID:15836428 supporting_text: Among a panel of ECM components, including glycosaminoglycans, photomedins preferentially bound to chondroitin sulphate-E and heparin. - reference_id: file:HORSE/OLFML2A/OLFML2A-uniprot.txt record_section: ["DR:PANTHER"] supporting_text: DR PANTHER; PTHR23192:SF29; OLFACTOMEDIN-LIKE PROTEIN 2A; 1. - reference_id: file:human/OLFML2A/OLFML2A-uniprot.txt record_section: ["CC:SUBUNIT"] supporting_text: 'SUBUNIT: Homodimer. Binds to heparin and chondroitin sulfate E.' core_functions: - description: Secreted olfactomedin-domain glycoprotein that binds the sulfated glycosaminoglycans chondroitin sulfate E and heparin in the extracellular space. This activity is inferred for horse from the mouse ortholog in PANTHER subfamily SF29 and applies to the leader-bearing product of the locus. The physiological consequence of the binding is unknown. molecular_function: id: GO:0050840 label: extracellular matrix binding locations: - id: GO:0005576 label: extracellular region supported_by: - reference_id: PMID:15836428 supporting_text: Among a panel of ECM components, including glycosaminoglycans, photomedins preferentially bound to chondroitin sulphate-E and heparin. - reference_id: file:HORSE/OLFML2A/OLFML2A-bioinformatics/RESULTS-rereview.md supporting_text: The horse locus encodes a leader-bearing product. suggested_questions: - question: Are the leaderless horse OLFML2A transcripts (A0A9L0SKW1, A0A3Q2LAT7, RefSeq X2-X4) translated, and if so, where do their products go? RefSeq X1 shows that the locus encodes a signal-peptide-bearing product. The leaderless models begin at a different N-terminus (MDSQ-VFGD) in place of the leader. experts: [] - question: Is the 22-residue segment opposite human residues 123-144, which only the A0A9L0SKW1 model lacks, an alternatively spliced exon? Does its loss affect the N-terminal cysteine-motif region or dimerization? experts: [] - question: Is the equine protein, like human and mouse photomedin-1, cleaved after secretion and deposited in a defined tissue compartment - and is the equine kidney expression podocyte-restricted as in human? experts: [] - question: Is the PAINT signal-transduction assertion at the olfactomedin family root (PTN000573635) meant to apply to OLFML2A? It has no OLFML2A-specific support, and horse A0A9L0SKW1 does not carry that IBA. experts: [] suggested_experiments: - hypothesis: The equine OLFML2A locus mainly produces the signal-peptide-bearing transcript (RefSeq XP_023484611.2), and leaderless models such as A0A9L0SKW1 are minor or untranslated alternative products. description: 5-prime RACE and long-read sequencing of OLFML2A transcripts from horse retina and kidney to establish the true translation start and internal exon structure, together with ribosome profiling or targeted proteomics to test which N-terminus is translated. experiment_type: transcript 5-prime mapping / gene-model validation - hypothesis: Whichever equine form is real, it enters the secretory pathway and is released as a disulfide-bonded dimer that binds chondroitin sulfate E and heparin. description: Express tagged versions of the selected 599-residue sequence and of any transcript-verified signal-peptide-bearing form in a mammalian cell line; assay medium versus lysate by western blot for secretion, non-reducing versus reducing SDS-PAGE for disulfide-linked dimers, and glycosaminoglycan affinity chromatography against a panel including chondroitin sulfate E and heparin, with human OLFML2A as the positive control. experiment_type: secretion and glycosaminoglycan-binding assay - hypothesis: Equine OLFML2A occupies the same tissue niches as the human protein - photoreceptor outer segment and podocyte major processes. description: Immunohistochemistry and immunoelectron microscopy on horse retina and kidney sections using an antibody raised against the conserved olfactomedin domain, with colocalization against vimentin in podocytes as in the human study. experiment_type: tissue immunolocalization references: - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: - statement: The extracellular-region annotation on this horse record is a vocabulary mapping from the UniProt subcellular-location keyword SL-0243, not an equine observation; it inherits whatever the sequence-based location assignment asserts and so cannot itself settle whether this protein form is secreted. supporting_text: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt reference_section_type: DATABASE_ENTRY reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Procedural GO reference describing the keyword-to-GO-term mapping pipeline. Correctly applied, but it is a mapping rule rather than evidence, which is why the annotation it produced is left UNDECIDED for a model lacking the signal peptide. - id: PMID:15836428 title: 'Identification and characterization of photomedins: novel olfactomedin-domain-containing proteins with chondroitin sulphate-E-binding activity.' full_text_unavailable: true findings: - statement: Photomedin-1 (OLFML2A) has a defined domain architecture with tandem CXCXCX9C motifs in the N-terminal region, a coiled-coil domain, and a C-terminal olfactomedin domain. supporting_text: We identified two novel olfactomedin-family proteins characterized by the presence of tandem CXCXCX9C motifs in the N-terminal region, a coiled-coil domain and an olfactomedin domain in the C-terminal region. reference_section_type: ABSTRACT - statement: Photomedin-1 is secreted as a disulphide-bonded dimer carrying O-linked carbohydrate chains and is proteolytically processed mid-molecule after secretion, so secretory entry is a prerequisite for the characterized mature form rather than an incidental detail. supporting_text: These proteins, named photomedin-1 and photomedin-2, were secreted as disulphide-bonded dimers (photomedin-1) or oligomers/multimers (photomedin-2) with O-linked carbohydrate chains, although photomedin-1 was proteolytically processed in the middle of the molecule after secretion. reference_section_type: ABSTRACT - statement: Among extracellular matrix components tested, the photomedins bound preferentially to chondroitin sulphate-E and heparin - a binding preference, not a demonstration of matrix assembly or of a signaling receptor. supporting_text: Among a panel of ECM components, including glycosaminoglycans, photomedins preferentially bound to chondroitin sulphate-E and heparin. reference_section_type: ABSTRACT - statement: In the retina, photomedin-1 is selectively expressed in the photoreceptor outer segment, distinguishing it from photomedin-2/OLFML2B, which is expressed in all retinal neurons. supporting_text: In the retina, photomedin-1 was selectively expressed in the outer segment of photoreceptor cells and photomedin-2 was expressed in all retinal neurons. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: The founding characterization of the photomedins and the source of the secretion, dimerization and glycosaminoglycan-binding claims. Abstract-only in the local cache. Mouse recombinant protein work; transfer to the equine model is not asserted, and the paper itself frames the glycosaminoglycan result as binding rather than matrix assembly. - id: PMID:22913984 title: Neuronal proteins are novel components of podocyte major processes and their expression in glomerular crescents supports their role in crescent formation. full_text_unavailable: true findings: - statement: OLFML2A is enriched in the glomerulus, establishing a kidney protein pool distinct from the retinal one. supporting_text: Unexpectedly, the survey found expression of three neuronal proteins (Huntingtin interacting protein 1 (Hip1), neurofascin (Nfasc), and olfactomedin-like 2a (Olfml2a)), all enriched in the glomerulus. reference_section_type: ABSTRACT - statement: Within the glomerulus OLFML2A is expressed exclusively by podocytes and localizes to their major processes, verified by four independent methods including immunoelectron microscopy. supporting_text: These proteins were expressed exclusively by podocytes, wherein they localized to major processes as verified by RT-PCR, western blotting, immunofluorescence, and immunoelectron microscopy. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: The source behind the human UniProt tissue-specificity and podocyte-localization annotations. Abstract-only in the local cache. Human and rodent kidney tissue; cited as characterized mammalian biology under consideration for transfer, not as equine evidence. - id: PMID:18757743 title: Transcriptome-based systematic identification of extracellular matrix proteins. full_text_unavailable: true findings: - statement: The screen that placed OLFML2A among extracellular matrix proteins assayed candidates for matrix-assembling activity, matrix interactions, glycosaminoglycan modification and cell adhesion, so which of those a given hit satisfied has to be traced per gene before a matrix-organization claim can be made for it. supporting_text: These assays screened the candidate proteins for ECM-assembling activities, interactions with other ECM molecules, modifications with glycosaminoglycans, and cell-adhesive activities, and were then complemented with immunohistochemical analysis. reference_section_type: ABSTRACT reference_review: relevance: LOW correctness: VERIFIED review_notes: Background for the extracellular-matrix classification of this family. The cached abstract does not name OLFML2A or report which assay it passed, so it is cited only for the screen design. Per the gene notes, a specific matrix-organization claim needs the screen traced at gene and assay level first. - id: file:HORSE/OLFML2A/OLFML2A-uniprot.txt title: 'UniProtKB A0A9L0SKW1: selected horse OLFML2A protein model' findings: - statement: The horse OLFML2A entry is an unreviewed 599-residue TrEMBL record whose protein name derives solely from an Ensembl gene model, with no equine experimental characterization. record_section: [DE] supporting_text: 'SubName: Full=Olfactomedin like 2A {ECO:0000313|Ensembl:ENSECAP00000076704.1};' reference_section_type: DATABASE_ENTRY - statement: The record carries an olfactomedin-like domain signature, which is what secures family identity independently of the missing N-terminal features. record_section: ["DR:InterPro"] supporting_text: 'InterPro; IPR003112; Olfac-like_dom.' reference_section_type: DATABASE_ENTRY - statement: The selected horse record carries the Secreted keyword, but it is assigned by an ARBA family rule rather than by a signal-peptide feature on this sequence. supporting_text: 'KW Secreted {ECO:0000256|ARBA:ARBA00022525}.' reference_section_type: DATABASE_ENTRY reference_review: relevance: HIGH correctness: VERIFIED review_notes: Source record for the reviewed protein form. Naming and domain assignment are computational (Ensembl/InterPro/Pfam); they establish family identity but no equine function or localization. - id: file:HORSE/OLFML2A/OLFML2A-bioinformatics/RESULTS.md title: 'OLFML2A: horse-human sequence comparison' findings: - statement: The horse sequence is a close counterpart of human OLFML2A over nearly its whole length (91.3% identity, 598 paired residues, 99.8% horse coverage), so the differences are localized rather than global. supporting_text: The downloaded human Q68BL7 sequence (652 residues) and selected horse A0A9L0SKW1 sequence (599 residues) share 91.3% identity among 598 paired residues. reference_section_type: RESULTS - statement: The alignment places a 26-residue gap opposite the human signal peptide and a further 22-residue internal deletion opposite human residues 123-144; the latter ends upstream of the predicted human coiled-coil at residues 157-183. supporting_text: The global alignment pairs the initiating horse methionine with human residue 1, then places a 26-residue gap opposite human residues 2–27. reference_section_type: RESULTS - statement: The analysis explicitly declines to conclude that the horse gene product is intracellular, or that the prediction pipeline was fed a leaderless sequence - the discrepancy is recorded as a model limitation, not a demonstrated biological difference. supporting_text: It does not establish that the horse gene is intracellular, or that the original ProtNLM input lacked the leader. reference_section_type: RESULTS reference_review: relevance: HIGH correctness: VERIFIED review_notes: Reproducible pairwise alignment with retained full output and sequence hashes; computed, not hardcoded. It localizes the problem to the signal peptide and one internal segment, which is the basis for the UNDECIDED action on the extracellular-region annotation. - id: file:human/OLFML2A/OLFML2A-uniprot.txt title: 'UniProtKB Q68BL7: human OLFML2A/photomedin-1 (curated reference ortholog)' findings: - statement: Human OLFML2A is annotated as secreted, and the annotation is itself a similarity transfer from the mouse protein rather than a direct human observation. record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: 'SUBCELLULAR LOCATION: Secreted {ECO:0000250|UniProtKB:Q8BHP7}.' reference_section_type: DATABASE_ENTRY - statement: Secretion depends on a signal peptide occupying human residues 1-27, precisely the region for which the horse model has no counterpart. record_section: ["FT:SIGNAL"] supporting_text: SIGNAL 1..27 reference_section_type: DATABASE_ENTRY - statement: The human protein is a homodimer that binds heparin and chondroitin sulfate E. record_section: ["CC:SUBUNIT"] supporting_text: 'SUBUNIT: Homodimer. Binds to heparin and chondroitin sulfate E.' reference_section_type: DATABASE_ENTRY - statement: Human UniProt annotates residues 28-652 as the mature post-cleavage OLFML2A chain. record_section: ["FT:CHAIN"] supporting_text: CHAIN 28..652 reference_section_type: DATABASE_ENTRY - statement: The olfactomedin-like domain spans human residues 394-652, i.e. the conserved C-terminal two-thirds that the horse model does retain. record_section: ["FT:DOMAIN"] supporting_text: DOMAIN 394..652 reference_section_type: DATABASE_ENTRY - statement: Human OLFML2A also localizes to podocyte major processes and colocalizes with vimentin through podocyte development, a kidney pool separate from the retinal expression. record_section: ["CC:SUBCELLULAR LOCATION"] supporting_text: Note=Localizes to the podocyte major processes. Colocalized with the reference_section_type: DATABASE_ENTRY - statement: The human gene has three annotated splice isoforms, which is a further reason a single divergent N-terminus in another species is better treated as a transcript-model question than as evidence of lost secretion. record_section: ["CC:ALTERNATIVE PRODUCTS"] supporting_text: Event=Alternative splicing; Named isoforms=3; reference_section_type: DATABASE_ENTRY reference_review: relevance: HIGH correctness: VERIFIED review_notes: Curated Swiss-Prot record for the human ortholog. Note that the Secreted, homodimer and post-secretion-cleavage annotations carry ECO:0000250 (sequence-similarity transfer from mouse Q8BHP7) rather than direct human experimental codes; the podocyte localization is the experimentally supported part. - id: file:HORSE/OLFML2A/OLFML2A-bioinformatics/RESULTS-rereview.md title: 'OLFML2A horse gene-model comparison (re-review, 2026-10-20)' findings: - statement: The horse OLFML2A locus encodes a leader-bearing 650-residue RefSeq product (XP_023484611.2) that matches human canonical isoform 1. The benchmark A0A9L0SKW1 is one of several leaderless alternative models, and it additionally lacks the segment opposite human 123-144. supporting_text: The benchmark accession A0A9L0SKW1 is one of several leaderless alternative models of the same gene. reference_section_type: RESULTS reference_review: relevance: HIGH correctness: VERIFIED review_notes: Reproducible script (compare_sequences_rereview.py) that fetches the sequences live and writes its raw output to RESULTS-rereview.json. It supersedes the earlier RESULTS.md for the gene-model question; RESULTS.md is retained and is still cited.