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"
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Endothelial-specific deletion of the mouse ortholog reduces brain uptake of injected radiolabelled choline, establishing that the transporter performs choline movement at the blood-brain barrier in vivo.
"There was a significant reduction of radioactive signals in the brain of EcMfsd7c-KO mice compared to controls."
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Heme is not perturbed by loss of the mammalian ortholog, and the authors state that the earlier heme-import report has not been confirmed.
"heme and bilirubin levels in fetal brains were comparable between Mfsd7c–/– and WT embryos"
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"
Molecular mechanism of choline and ethanolamine transport in humans.
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Human FLVCR1 and FLVCR2 are uniporters that move choline and ethanolamine down their gradients without coupling to sodium or pH.
"Our findings suggest that both FLVCR1 and FLVCR2 operate as uniporters, facilitating downhill ligand transport independent of sodium or pH gradients."
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Both transporters are localized at the plasma membrane by confocal imaging.
"Confocal imaging shows that FLVCR1 and FLVCR2 are localized at the plasma membrane"
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Choline and ethanolamine are the primary transport substrates of both proteins, and a shared binding-site glutamine is required for transport of both.
"alanine substitution of the analogous Q191FLVCR2 residue abolishes the transport of both ethanolamine and choline in FLVCR2"
The Fowler syndrome-associated protein FLVCR2 is an importer of heme.
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Human FLVCR2 binds hemin-agarose in a hemin-competable manner.
"FLVCR2 binds to hemin-conjugated agarose, and binding is competed by free hemin"
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The same study states that FLVCR2, unlike FLVCR1, does not export heme, and proposes an import rather than an export role.
"a report by Quigley and colleagues ( 37 ) clearly shows that FLVCR2 does not export heme."
Deficiency of MFSD7c results in microcephaly-associated vasculopathy in Fowler syndrome.
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The mouse ortholog Mfsd7c is expressed in the blood-brain barrier.
"We identified the mouse ortholog Mfsd7c as a gene expressed in the blood-brain barrier."
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Loss of the mouse ortholog inhibits angiogenic growth of CNS blood vessels and causes microcephaly-associated vasculopathy.
"results indicate that MFSD7c is required for the normal growth of CNS blood vessels and that ablation of this gene results in microcephaly-associated vasculopathy in mice and humans."