FGF12

Summary: The inherited receptor-binding loss and later direct short-product binding remain unreconciled.

Reason: PAINT negates GO:0005104 at the verified target ancestor PTN000160077. This supports the historical negative interpretation, but its exported source points to the positive ancestral node rather than identifying an independent experiment. PMID12815063 used engineered short human FHF1b C144A and cellular mitogenesis/antagonism readouts. PMID32357892 later measured direct FGFR binding with short human FHF1b. Two curation channels do not establish independent replication or erase conflicting primary evidence. Preserve NOT and P61328-2 while construct and assay differences remain unresolved.

Summary: Specify the functional sodium-channel interaction demonstrated for human FGF12B.

Reason: PMID22705208 uses FGF13 for the crystal complex, but directly tests human FGF12B (NM_004113) with NaV1.5 by calorimetry, co-purification and electrophysiology. Figure 3 and Table 2 connect binding-site charge swaps to altered channel inactivation. This supports sodium channel regulator activity, already represented in the imported review. The FGF13 crystal is not presented as a solved FGF12 structure.

Proposed replacements: sodium channel regulator activity

Summary: Retain the curated FGF12 interaction with DCTD as non-core.

Reason: The preserved UniProt INTERACTION block lists the exact FGF12/P32321 pair with IntAct provenance and NbExp=3, consistent with this imported IPI context. The cited proteome-scale interaction study supplies screen provenance; its individual supplementary clone row was not independently re-extracted here. No supported molecular-role refinement follows from the partner name alone. Retain the curated interaction without assigning the partner's function to FGF12, following the ClinGen binding instruction.

Summary: Retain the curated FGF12 interaction with COIL as non-core.

Reason: The preserved UniProt INTERACTION block lists the exact FGF12/P38432 pair with IntAct provenance and NbExp=3, consistent with this imported IPI context. The cited proteome-scale interaction study supplies screen provenance; its individual supplementary clone row was not independently re-extracted here. No supported molecular-role refinement follows from the partner name alone. Retain the curated interaction without assigning the partner's function to FGF12, following the ClinGen binding instruction.

Summary: Retain the curated FGF12 interaction with IKZF1 as non-core.

Reason: The preserved UniProt INTERACTION block lists the exact FGF12/Q13422 pair with IntAct provenance and NbExp=3, consistent with this imported IPI context. The cited proteome-scale interaction study supplies screen provenance; its individual supplementary clone row was not independently re-extracted here. No supported molecular-role refinement follows from the partner name alone. Retain the curated interaction without assigning the partner's function to FGF12, following the ClinGen binding instruction.

Summary: Retain the curated FGF12 interaction with ZNF460 as non-core.

Reason: The preserved UniProt INTERACTION block lists the exact FGF12/Q14592 pair with IntAct provenance and NbExp=3, consistent with this imported IPI context. The cited proteome-scale interaction study supplies screen provenance; its individual supplementary clone row was not independently re-extracted here. No supported molecular-role refinement follows from the partner name alone. Retain the curated interaction without assigning the partner's function to FGF12, following the ClinGen binding instruction.

Summary: Retain the curated FGF12 interaction with LZTS2 as non-core.

Reason: The preserved UniProt INTERACTION block lists the exact FGF12/Q9BRK4 pair with IntAct provenance and NbExp=3, consistent with this imported IPI context. The cited proteome-scale interaction study supplies screen provenance; its individual supplementary clone row was not independently re-extracted here. No supported molecular-role refinement follows from the partner name alone. Retain the curated interaction without assigning the partner's function to FGF12, following the ClinGen binding instruction.

Summary: Retain the curated FGF12 interaction with DACH1 isoform2 as non-core.

Reason: The preserved UniProt INTERACTION block lists the exact FGF12/Q9UI36-2 pair with IntAct provenance and NbExp=3, consistent with this imported IPI context. The cited proteome-scale interaction study supplies screen provenance; its individual supplementary clone row was not independently re-extracted here. No supported molecular-role refinement follows from the partner name alone. Retain the curated interaction without assigning the partner's function to FGF12, following the ClinGen binding instruction.

Summary: Retain the curated FGF12B/P61328-2 interaction with ZNF79 as non-core.

Reason: The preserved UniProt INTERACTION block lists the exact FGF12B/P61328-2/Q15937 pair with IntAct provenance and NbExp=3, consistent with this imported IPI context. The cited proteome-scale interaction study supplies screen provenance; its individual supplementary clone row was not independently re-extracted here. No supported molecular-role refinement follows from the partner name alone. Retain the curated interaction without assigning the partner's function to FGF12, following the ClinGen binding instruction.

Summary: Retain the curated FGF12B/P61328-2 interaction with RNF151 as non-core.

Reason: The preserved UniProt INTERACTION block lists the exact FGF12B/P61328-2/Q2KHN1 pair with IntAct provenance and NbExp=3, consistent with this imported IPI context. The cited proteome-scale interaction study supplies screen provenance; its individual supplementary clone row was not independently re-extracted here. No supported molecular-role refinement follows from the partner name alone. Retain the curated interaction without assigning the partner's function to FGF12, following the ClinGen binding instruction.

Summary: Retain the curated FGF12B/P61328-2 interaction with CT45A1 as non-core.

Reason: The preserved UniProt INTERACTION block lists the exact FGF12B/P61328-2/Q5HYN5 pair with IntAct provenance and NbExp=3, consistent with this imported IPI context. The cited proteome-scale interaction study supplies screen provenance; its individual supplementary clone row was not independently re-extracted here. No supported molecular-role refinement follows from the partner name alone. Retain the curated interaction without assigning the partner's function to FGF12, following the ClinGen binding instruction.

Summary: Retain the curated FGF12B/P61328-2 interaction with RP9 as non-core.

Reason: The preserved UniProt INTERACTION block lists the exact FGF12B/P61328-2/Q8TA86 pair with IntAct provenance and NbExp=3, consistent with this imported IPI context. The cited proteome-scale interaction study supplies screen provenance; its individual supplementary clone row was not independently re-extracted here. No supported molecular-role refinement follows from the partner name alone. Retain the curated interaction without assigning the partner's function to FGF12, following the ClinGen binding instruction.

Summary: Retain the curated FGF12B/P61328-2 interaction with STAC3 as non-core.

Reason: The preserved UniProt INTERACTION block lists the exact FGF12B/P61328-2/Q96MF2 pair with IntAct provenance and NbExp=3, consistent with this imported IPI context. The cited proteome-scale interaction study supplies screen provenance; its individual supplementary clone row was not independently re-extracted here. No supported molecular-role refinement follows from the partner name alone. Retain the curated interaction without assigning the partner's function to FGF12, following the ClinGen binding instruction.

Summary: Retain the curated FGF12B/P61328-2 interaction with THAP1 as non-core.

Reason: The preserved UniProt INTERACTION block lists the exact FGF12B/P61328-2/Q9NVV9 pair with IntAct provenance and NbExp=3, consistent with this imported IPI context. The cited proteome-scale interaction study supplies screen provenance; its individual supplementary clone row was not independently re-extracted here. No supported molecular-role refinement follows from the partner name alone. Retain the curated interaction without assigning the partner's function to FGF12, following the ClinGen binding instruction.

Summary: Retain the curated FGF12B/P61328-2 interaction with RBAK as non-core.

Reason: The preserved UniProt INTERACTION block lists the exact FGF12B/P61328-2/Q9NYW8 pair with IntAct provenance and NbExp=3, consistent with this imported IPI context. The cited proteome-scale interaction study supplies screen provenance; its individual supplementary clone row was not independently re-extracted here. No supported molecular-role refinement follows from the partner name alone. Retain the curated interaction without assigning the partner's function to FGF12, following the ClinGen binding instruction.

Summary: Retain the curated FGF12B/P61328-2 interaction with DACH1 isoform2 as non-core.

Reason: The preserved UniProt INTERACTION block lists the exact FGF12B/P61328-2/Q9UI36-2 pair with IntAct provenance and NbExp=3, consistent with this imported IPI context. The cited proteome-scale interaction study supplies screen provenance; its individual supplementary clone row was not independently re-extracted here. No supported molecular-role refinement follows from the partner name alone. Retain the curated interaction without assigning the partner's function to FGF12, following the ClinGen binding instruction.

Summary: Retain the curated FGF12B/P61328-2 interaction with GRIP1 isoform3 as non-core.

Reason: The preserved UniProt INTERACTION block lists the exact FGF12B/P61328-2/Q9Y3R0-3 pair with IntAct provenance and NbExp=3, consistent with this imported IPI context. The cited proteome-scale interaction study supplies screen provenance; its individual supplementary clone row was not independently re-extracted here. No supported molecular-role refinement follows from the partner name alone. Retain the curated interaction without assigning the partner's function to FGF12, following the ClinGen binding instruction.

Summary: FGF12 associates with TCOF1 in nucleolar protein complexes; preserve the imported FGF12B interaction context.

Reason: PMID:36411431 detects TCOF1 among recombinant FGF12-His pull-down partners and confirms recovery by immunoblotting (Results lines 185–196; Figures 1B and 2A). Tagged cellular FGF12 also co-purifies and gives proximity signals with TCOF1 (lines 208–218; Figure 3A–D). These are positive association results, not a purified binary reconstitution. Preserve imported P61328-2 and partner Q13428. The unchanged UniProt INTERACTION record assigns the same pair to P61328-2; this records curated provenance rather than a separate experiment. Cellular constructs are explicitly a isoforms in Methods line 102. Recombinant short-chain numbering at line 108 is not a complete sequence-to-accession proof; do not transfer the tagged-a localization findings to isoform 2. A more specific scaffold-binding function is not established: the official term describes binding a signaling scaffold, whereas this paper establishes nucleolar co-complex association and leaves its functional output unresolved. Retain the supported generic interaction as non-core under the ClinGen instruction.

Summary: Extracellular location remains unresolved for the inaccessible historical source.

Reason: The 1999 full article remains unavailable; its abstract and revised U76381.2 establish FGF12b identity, not an inspectable extracellular-location assay. PAINT negates GO:0005576 at PTN000160077, and PMID8790420 Figure 7 found no detectable release of its long construct in 293 cells. Conversely, PMID38468333 detects extracellular tagged FGF12 under stress/galectin-perturbation conditions. Neither a missing signal peptide nor the ancestral loss establishes universal non-release. Retain source-specific uncertainty without over-ruling an unread paper or transferring tagged-a results to the historical short product.

Summary: Retain the inherited nuclear activity context as non-core.

Reason: The positive nucleus IBD at PTN000160077 lies on the recovered P61328 ancestry path. Human FHF1 nuclear localization is independently demonstrated in PMID8790420 Figure 8; PMID36411431 further supports a nuclear/nucleolar pool. The IBA is_active_in assertion is retained as a curated ancestral judgment, not reduced to an imaging measurement. Localization does not establish identical activity or distribution of both natural products. The whole-tree download is incomplete.

Summary: Human FHF1 accumulates in the nucleus in the original 293-cell assay.

Reason: The recovered original demonstrates nuclear localization of transfected human FHF1 and maps an amino-terminal nuclear localization signal using deletion and beta-galactosidase fusion constructs (Methods p. 9851; Results p. 9856; Figure 8). This is a positive localization result, not a claim that every natural splice product is exclusively nuclear. The long amino-terminal construct is not evidence that the short product has the same targeting sequence.

Summary: Retain the supported nuclear location from the UniProt vocabulary mapping.

Reason: The preserved UniProt SUBCELLULAR LOCATION statement maps SL-0191 to nucleus with ECO:0000305. This is curator inference rather than an HPA experiment. Original human FHF1 localization in PMID8790420 Figure 8 and tagged-a nucleolar findings in PMID36411431 support this secondary location without assigning it to all splice products.

Summary: The historical nuclear-location statement is directly supported by the original experiments.

Reason: The same original Figure 8 and p. 9856 Results establish nuclear accumulation of expressed human FHF1 in 293 cells. Preserve this TAS source separately from row 20 IDA. N-terminal artificial deletions and beta-galactosidase fusions are not natural splice products; nuclear residence is retained as a secondary location.

Summary: FGF12 has a supported nucleolar pool in the human cell systems studied.

Reason: PMID:36411431 reports tagged FGF12 nucleolar enrichment by imaging, dyskerin colocalization and nucleolar fractionation (Results lines 191–193; Figure 1D–F; Methods lines 102, 120–122 and 146–148). Partner proximity was also reported in HEK293 cells without ectopic FGF12 (line 216; supplementary Figure S4 caption, line 269). Retain this secondary location without implying identical localization in every endogenous isoform or cell type. The tagged localization construct is the a isoform, and the endogenous-antibody result is not isoform-resolved. Nucleolar localization does not itself demonstrate ribosome-biogenesis participation.

Summary: Cytoplasmic activity is consistent with intracellular sodium-channel regulation.

Reason: The positive cytoplasm IBD at PTN000160075 is an ancestor of the actual P61328 leaf. Binding to the cytoplasmic channel tail and functional modulation are supported by the rat FHF1B study and independent human FGF12B experiments in PMID22705208. Nuclear enrichment does not contradict cytoplasmic activity. The complete canonical target sequence matches the family MSA; no whole-tree or short-product alignment claim is made.

Summary: The 1999 signal-transduction claim remains source-specific uncertainty.

Reason: The accessible abstract and official sequence record establish a heart-derived FGF12b cDNA, not an inspectable signaling assay. Full Methods/Results remain unavailable; retain UNDECIDED rather than infer the paper lacks such experiments. Later receptor signaling is a separately adjudicated supporting source, not a replacement for reading this one.

Summary: The 1996 source proposes FHF signaling but does not establish its signaling mechanism.

Reason: Full original Methods, Results and Discussion were recovered and read. Page 9857 explicitly presents receptor signaling as a presumption from FGF homology and calls for future functional assays; Figures 4–8 measure expression and localization rather than a receptor-to-cell-state signaling response. This is an unresolved source-specific attribution, not a conclusion that FGF12 cannot signal. Later PMID32357892 demonstrates receptor-dependent signaling, but does not turn the historical hypothesis into an experiment in the cited original.

Summary: IB2 binding is positive, but the specific JNK-cascade interpretation remains unresolved.

Reason: The original Figure 3 demonstrates direct binding to a murine IB2 fragment. The paper discusses p38 recruitment through IB2; binding a scaffold does not identify the JNK-specific step. Preserve the IPI assertion while its pathway interpretation remains uncertain.

Summary: The verified electronic rule match does not establish physiological cell-cell signaling.

Reason: ARBA00028183 condition set 21 actually matches the target FunFam and Haplorrhini lineage. PMID32357892 demonstrates direct binding and receptor-dependent responses to exogenously supplied short FHF1b, but not a physiological producer-to-recipient signaling chain. PMID38468333 provides bounded tagged-protein release evidence, not the missing coupled transfer experiment. The PTN000160077 losses of extracellular location, receptor binding and receptor signaling also require reconciliation. Use uncertainty rather than non-core acceptance, without falsely denying every extracellular detection or receptor interaction.

Summary: The 1999 cell-to-cell signaling claim remains source-specific uncertainty.

Reason: No relevant recipient-cell assay is accessible in the abstract-only cache. The resolved FGF12b sequence identity is not functional evidence. Preserve the curator source and defer the claim until the original assay or an explicitly matched independent claim can be evaluated.

Summary: Cell-to-cell signaling remains a proposed interpretation in this source.

Reason: The original p. 9857 Discussion hypothesizes local growth/survival-factor action and a possible alternative release pathway, while Figure 7 tests no detectable secretion of the expressed FHF1 construct in 293 cells. No donor-to-recipient signaling assay is reported in the fully read original. The negative secretion result is condition-specific and does not exclude all extracellular FGF12 activity or later positive results.

Summary: Retain the broad developmental role as non-core.

Reason: ARBA00027428 condition set 46 matches the target FunFam and Homo lineage. The independently verified positive neurogenesis IBD at PTN000160075 supplies curated phylogenetic support for a descendant developmental process. Retain this broader role without claiming that neural expression, epilepsy or altered excitability alone demonstrates a developmental step. This does not make the 1996 expression experiments a functional test.

Summary: Developmental neural expression is positive, but the source does not resolve a developmental function.

Reason: Mouse transcript mapping in Figures 4–5 and p. 9854 establishes neural expression during development; adult macaque immunoreactivity in Figure 6 has stated possible FHF-family cross-reactivity. The final Discussion p. 9857 explicitly identifies nervous-system development/function as a hypothesis requiring functional assays and gene manipulation. Expression does not identify the step performed by FGF12 during development. No biological contradiction or wrong-gene claim is inferred.

Summary: Heart-enriched expression does not alone establish participation in heart development.

Reason: The accessible abstract reports human heart cDNA and Northern expression. This does not identify a developmental step performed by FGF12, but unavailable full text prevents asserting that no such evidence was reported. Keep UNDECIDED without equating heart expression with developmental causality.

Summary: The family-based growth-factor assignment overlooks the curated loss at the FHF ancestor.

Reason: ARBA00093068 condition set 1 and IPR002209 mechanically match FGF12. However, PAINT negates GO:0008083 at PTN000160077 on the target path, blocking the positive growth-factor inference from PTN000160075. This term requires stimulation of cell growth or proliferation. PMID32357892 supplies receptor-binding and survival results but no mitogenic response in its tested systems. With the earlier assays and curated loss, this supports flagging the broad electronic assignment as over-annotation. This concerns growth/proliferation, not a denial of every receptor interaction, survival effect or release condition.

Summary: The inaccessible 1999 growth-factor claim retains source-specific uncertainty despite contrary lineage evidence.

Reason: U76381.2 resolves the FGF12b identity, but the original relevant assays remain inaccessible. The GO:0008083 IRD at PTN000160077 and later nonmitogenic findings argue against transferring activity from the family name. They do not reveal what the 1999 paper measured or resolve its revised construct sequence. Retain UNDECIDED for this unread TAS source; the separately traceable electronic mapping and fully read 1996 hypothesis are flagged as over-annotation. Receptor activation or survival alone does not establish growth/proliferation.

Summary: The fully read 1996 hypothesis does not establish growth-factor activity and conflicts with the lineage loss.

Reason: PMID8790420 proposes growth/survival-factor roles from FGF homology in Discussion p.9857 without an FHF1-dependent growth/proliferation experiment. PAINT negates GO:0008083 at target ancestor PTN000160077, and the studied human short-product assays in PMID12815063 and PMID32357892 do not demonstrate mitogenesis. This positive functional annotation overstates its fully read source. The later receptor-binding and survival findings are distinct endpoints and are not denied.

Summary: Retain experimentally supported heparin affinity as a non-core biochemical property.

Reason: Original Figure 1 directly demonstrates heparin affinity of the engineered human short FHF1b preparation. This positive binding observation is distinct from physiological secretion or receptor activation.

Summary: The curated receptor-signaling loss requires reconciliation with later receptor-activation measurements.

Reason: PAINT negates GO:0008543 at target ancestor PTN000160077. This supports the older negative interpretation but is not an identified second direct experiment in the exported source. The historical short-product assay tested mitogenesis/antagonism; PMID32357892 reports FGFR-dependent receptor and ERK activation while still finding no proliferation. These endpoints differ. Preserve the imported NOT and P61328-2 context with an unresolved review rather than accept an unconditional negative by counting curated channels and setting aside the later primary result.

Summary: The cited neural-crest experiments establish the KBTBD8–NOLC1/TCOF1 pathway, but do not establish FGF12 participation in neural crest cell development.

Reason: The full cached PMID:26399832 Results, relevant Methods and extended captions were read. Human embryonic stem-cell and Xenopus experiments concern CUL3/KBTBD8 and NOLC1/TCOF1 (Results lines 68–86, especially line 76/Figure 3; Methods lines 98, 122–136 and 160; Extended Data Figure 6, line 256). No FGF12-targeted developmental result was identified in this scope. PMID:36411431 establishes FGF12 association with those proteins in U2OS/HEK293 cells, but does not demonstrate FGF12 work in progression from neural-crest commitment to differentiated cells. Extending the partners' developmental function to FGF12 overstates this evidence. This judgment is not based on title/abstract alone and does not assert a negative FGF12 phenotype, an experimentally demonstrated wrong-gene annotation or a literature-wide absence of such a role.

Summary: Sodium-channel regulation is a supported inherited core activity.

Reason: The positive sodium-channel regulator IBD at PTN000160077 is on the actual target ancestry path, and the canonical 243-residue target matches the family MSA. Human FGF12B functional binding measurements in PMID22705208 and the variant-dependent excitability study PMID27164707 support the inherited activity. The rat FHF1B donor experiment is separately identified in PMID12401812. No target-specific loss or divergence is established; one gating direction is not generalized to all channels or products.

Summary: Sodium-channel modulation is a core FGF12 function.

Reason: The original Methods identify rat FHF1B (AF348446), distinct from the human NaV1.5 channel and HEK293 host. Binding and electrophysiological modulation support this conserved ISS function; PMID22705208 independently tests human FGF12B and channel gating. Neither assay assigns one gating direction to all channel/isoform combinations.

Summary: Retain the curated neurogenesis inference as a developmental, non-core role.

Reason: The positive neurogenesis IBD at PTN000160075 lies on the actual target ancestry path and the canonical target matches the family MSA. No target-specific loss or divergence was identified. This retains the PAINT curator's ancestral judgment; expression and seizure phenotypes do not independently establish neuron generation. Underlying descendant developmental experiments were not all rereviewed, and the whole-tree download is incomplete. Node depth, donor breadth and self-WITH are not reasons to reject the inference.

Summary: FGF12 supports NOLC1–TCOF1 complex association, but its contribution to productive ribosome biogenesis remains unresolved.

Reason: PMID:26399832 establishes a NOLC1/TCOF1 platform linking RNA polymerase I and ribosome-modification machinery (Results lines 78–86/Figures 4–5), without a FGF12-specific intervention identified in the full cached read scope. PMID:36411431 supplies genuine FGF12 evidence: association with both partners and loss of their proximity signal following FGF12 depletion (lines 208–240; Figures 3–4). That positive complex-assembly contribution could support a scaffold role and is not dismissed because FGF12 is nonenzymatic. However, the study does not connect this FGF12-dependent result to synthesis, processing, assembly or transport of ribosomal subunits. Its Discussion explicitly leaves ribosome-biogenesis versus DNA-damage-response function unresolved (line 250). Retain uncertainty rather than converting partner function or complex necessity alone into demonstrated FGF12 participation, or declaring the putative role false. PMID38468333 shows galectin-dependent changes in the pairwise nuclear associations, but its new perturbation targets galectin-1 and its nuclear-function model remains unresolved. A scaffold contribution could qualify without catalysis; the unresolved issue is the productive process served by these associations.

Summary: Retain the physical sodium-channel interaction supporting regulation.

Reason: The cited rat FHF1B work demonstrates binding to a sodium-channel cytoplasmic tail, and PMID22705208 independently measures human FGF12B–NaV1.5 interaction. This is transporter binding rather than FGF12-mediated sodium conductance. The donor/host species and natural versus engineered products remain distinct.

Summary: Retain the cardiac excitation context of NaV1.5 modulation as non-core.

Reason: Modulation of the cardiac sodium channel provides a mechanistic connection to cardiac excitation. The cited experiments used rat FHF1B and recombinant channels in heterologous cells; they did not record a contracting human cardiomyocyte action potential. Retain this contextual NAS inference without presenting it as a direct contraction assay or the sole defining function.

Summary: FGF12 regulates neuronal excitability through sodium-channel gating.

Reason: PMID27164707 combines a patient FGF12 variant with channel-gating measurements and zebrafish neural activity. Its Neuro2A experiments and ortholog overexpression model support the excitability mechanism; disease severity is not itself the annotation evidence. Preserve the distinction between human variant interpretation and the zebrafish B-type transgene.

Summary: FGF12 regulates sodium flux by modifying sodium-channel gating.

Reason: The rat FHF1B donor experiment changes NaV1.5 current inactivation through channel association. Human FGF12B binding/function measurements in PMID22705208 independently support conserved regulation. FGF12 is a channel regulator, not an ion-conducting pore.

Summary: Voltage-gated sodium-channel regulation is supported by the functional variant experiments.

Reason: The cited study tests FHF1A/FHF1B variants against wild-type proteins and reports altered NaV1.6 fast inactivation, with a separate zebrafish excitability phenotype. The evidence-coded UniProt FUNCTION statement records curation of this same study; it is not a second experiment. The review does not generalize one direction of gating change across all FGF12 products.