si:dkey-283b1.7 (ZFIN ZDB-GENE-120215-126, chromosome 3; RefSeq name Brorin) encodes a 242-residue predicted secreted protein of the brorin (VWC2/VWC2L) family. It has an N-terminal signal peptide, then a short linker and the family's conserved core of two chordin-like von Willebrand factor C (VWFC) cysteine-rich domains, followed by a short basic tail. All 20 core cysteines of human VWC2 are conserved, but the long N-terminal region that distinguishes VWC2 is absent, so the architecture resembles VWC2L. The core is about 55-60% identical to each of VWC2, VWC2L and zebrafish vwc2, which is much lower than the 84-89% identity between vwc2 and human or gar VWC2. PANTHER places it as a teleost-duplication co-ortholog of VWC2, paired with vwc2. Ensembl Compara instead gives it no gar or human ortholog, only a medaka one, and its chromosomal neighbourhood shows no conserved synteny with the gar vwc2 region. It is therefore a fast-evolving teleost member of the family whose exact origin is unresolved. Public RNA-Seq calls place its expression in retina and brain. No experimental study of the gene has been published. Its activity (BMP antagonism, as for Brorin) is inferred from family membership only.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005576 extracellular region | IBA GO_REF:0000033 | ACCEPT | Summary: Extracellular region (IBA, brorin family node). Reason: The protein has a predicted signal peptide and no transmembrane segment, and family members are secreted. PANTHER node PTN002921765 covers both VWC2 and VWC2L (MGI donors Vwc2 and Vwc2l). si:dkey-283b1.7 falls inside the family whichever of the two branches it belongs to, so the inference does not depend on the unresolved orthology. Supporting Evidence: file:DANRE/si_dkey-283b1.7/si_dkey-283b1.7-bioinformatics/RESULTS.md si:dkey-283b1.7 has a predicted signal peptide (residues 1-18) PMID:17400546 Mouse Brorin protein produced in cultured cells was efficiently secreted into the culture medium. |
| GO:0005576 extracellular region | IEA GO_REF:0000044 | ACCEPT | Summary: Extracellular region from the UniProt 'Secreted' keyword (ARBA). Reason: Consistent with the predicted signal peptide. Supporting Evidence: file:DANRE/si_dkey-283b1.7/si_dkey-283b1.7-bioinformatics/RESULTS.md si:dkey-283b1.7 has a predicted signal peptide (residues 1-18) |
| GO:0030514 negative regulation of BMP signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Negative regulation of BMP signaling pathway (IBA, brorin family node). Reason: BMP antagonism is shown for mouse Brorin and Brorin-like and for zebrafish vwc2. si:dkey-283b1.7 keeps the cysteine-rich core that carries the chordin-like domains, and nothing argues for loss of the function. It has not been tested for this gene. Its core is divergent (about 55-60% identity to other members), so the activity may differ quantitatively. PANTHER node PTN002921765 covers both VWC2 and VWC2L (MGI donors Vwc2 and Vwc2l). si:dkey-283b1.7 falls inside the family whichever of the two branches it belongs to, so the inference does not depend on the unresolved orthology. Supporting Evidence: file:DANRE/si_dkey-283b1.7/si_dkey-283b1.7-bioinformatics/RESULTS.md si:dkey-283b1.7 keeps all 20 core cysteines of human VWC2 PMID:17400546 The protein inhibited the activity of bone morphogenetic protein 2 (BMP2) and BMP6 in mouse preosteoblastic MC3T3-E1 cells. PMID:28448525 These results indicate that the overexpression of brorin leads to the inactivation of Bmp signaling. |
| GO:0032281 AMPA glutamate receptor complex | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: AMPA glutamate receptor complex (IBA from mouse Vwc2/Vwc2l proteomics). Reason: Mouse Brorin and Brorin-like are peripheral extracellular constituents of native AMPA receptor complexes. The family inference is reasonable and the gene is expressed in brain and retina, but there is no zebrafish test, and the divergent sequence gives no assurance that the AMPAR/Noelin interaction is kept. Non-core. Supporting Evidence: PMID:37591201 Brorin and Brorin-like have been consistently retrieved in previous anti-GluA APs PMID:37591201 were entirely deprived of both Nrn1 and Brorin (Figure 1D) file:DANRE/si_dkey-283b1.7/si_dkey-283b1.7-bioinformatics/RESULTS.md si:dkey-283b1.7 has Bgee RNA-Seq calls in retina, brain and whole larva |
| GO:0045202 synapse | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Synapse from the UniProt ARBA subcellular location rule. Reason: Follows from the AMPA receptor association of mammalian family members. Untested for this gene. Supporting Evidence: PMID:37591201 Brorin and Brorin-like have been consistently retrieved in previous anti-GluA APs |
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Download this section (compressed HTML)Q: Is si:dkey-283b1.7 the TGD ohnolog of vwc2 (PANTHER), a fast-evolving VWC2L-related copy, or a separate old family branch lost in tetrapods (Ensembl Compara gives it no gar or human ortholog)? Its chromosome 3 neighbourhood shows no conserved synteny with the gar vwc2 region. A phylogeny with more non-teleost fish (bichir, sturgeon, bowfin, elephant shark) and a search of the gar genome for an unannotated brorin-family gene would help decide.
Q: Where exactly is si:dkey-283b1.7 expressed in retina and brain, and does its domain overlap with vwc2 or vwc2l?
Q: Does the protein inhibit BMP signalling, like vwc2, despite its divergent core?
Experiment: Inject si:dkey-283b1.7 mRNA and score dorsalization and pSmad1/5/8, side by side with brorin (vwc2) mRNA; test secretion of a tagged protein in cultured cells.
Hypothesis: si:dkey-283b1.7 is a secreted BMP antagonist.
Type: overexpression / biochemical assay
Experiment: In situ hybridization and a CRISPR mutant with retinal histology and ERG readouts.
Hypothesis: si:dkey-283b1.7 acts in the retina.
Type: expression and loss-of-function
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