Gene Ontology annotation through association of InterPro records with GO terms
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
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Endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), mitochondrial membrane (GO:0031966), ethanolamine transmembrane transporter activity (GO:0034228), and transport across blood-brain barrier (GO:0150104) were transferred to zebrafish Flvcr2a by curator-judged sequence similarity to its mammalian orthologs (human FLVCR2 UniProtKB:Q9UPI3 and mouse Mfsd7c UniProtKB:Q91X85).
Annotation inferences using phylogenetic trees
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Phylogenetic inference within PANTHER families PTN000858905 and PTN000858822 supports heme transmembrane transporter activity (GO:0015232), heme binding (GO:0020037), heme export (GO:0097037), and membrane localization (GO:0016020).
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
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The UniProt Swiss-Prot subcellular location keywords SL-0097 (Endoplasmic reticulum membrane), SL-0039 (Cell membrane), and SL-0171 (Mitochondrion membrane) map Flvcr2a to endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), and mitochondrial membrane (GO:0031966).
Automatic assignment of GO terms using logical inference, based on inter-ontology links
Electronic Gene Ontology annotations created by ARBA machine learning models
MFSD7c functions as a transporter of choline at the blood-brain barrier.
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Mfsd7c-knockout mouse and cell-based assays established MFSD7c (Flvcr2) as a facilitative, electrogenic choline transporter at the blood-brain barrier whose choline transport function is conserved across vertebrates; Fowler syndrome missense mutations abolish or reduce this activity.
"MFSD7c is a choline transporter at the blood-brain barrier"
UniProtKB entry A0A0R4ILB2 for Danio rerio flvcr2a
Falcon deep research report (Edison Scientific Literature) for Danio rerio flvcr2a (mfsd7c-a)
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The zebrafish orthologs were directly tested: the two zebrafish MFSD7c isoforms (DaMfsd7c_a and DaMfsd7c_b)
show choline transport activity in heterologous assays, providing direct species-relevant support for choline
transport rather than inference from mammalian orthologs alone.
"zebrafish MFSD7c isoforms “DaMfsd7c_a” and “DaMfsd7c_b” show choline transport activity in heterologous assays"
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2024 structural/functional work in humans establishes that FLVCR1 and FLVCR2 mediate choline and ethanolamine
transport as facilitative uniporters performing downhill transport independent of sodium or pH gradients, with
substrate selectivity mediated by conserved aromatic (cation-pi) residues.
"A 2024 Nature study concludes that human **FLVCR1 and FLVCR2 mediate cellular transport of choline and ethanolamine** and that both operate as **uniporters**"
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The historical heme-import model (from 2010 hemin-binding and heme-analog uptake assays) is reframed by 2024
mechanistic work, which explicitly states that FLVCR2-mediated heme uptake has not been confirmed and prioritizes
choline/ethanolamine as the primary substrates; heme transport should be treated as a contested legacy hypothesis.
"The 2024 Nature paper explicitly notes that **FLVCR2-mediated heme uptake “has not been confirmed”**"
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In mammals MFSD7c is required for BBB choline handling: endothelial-specific knockout reduces brain uptake of
injected radiolabeled choline while peripheral organ signals remain comparable, and loss of MFSD7c/FLVCR2 causes
neurovascular developmental defects (brain angiogenic sprouting) relevant to Fowler syndrome.
"loss of MFSD7c reduces brain uptake of injected radiolabeled choline while leaving peripheral organ signals comparable"