id: Q07326
gene_symbol: PIGF
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PIGF (phosphatidylinositol-glycan biosynthesis class F protein) is a multi-pass
  endoplasmic reticulum membrane protein that acts as a non-catalytic accessory
  (stabilizing) subunit of the glycosylphosphatidylinositol (GPI) ethanolamine-phosphate
  transferases. It forms complexes with the catalytic transferases PIGO and PIGG,
  stabilizing them and being required for their activity; PIGO (with PIGF) adds the
  bridging ethanolamine phosphate (EtNP) to the third mannose of the GPI intermediate,
  and PIGG (with PIGF) adds EtNP to the second mannose. Through these complexes PIGF
  participates in the late steps of GPI-anchor biosynthesis in the ER. PIGF itself
  has no independent enzymatic activity, and the two transferases compete for the shared
  PIGF stabilizer. Loss-of-function of PIGF causes an autosomal-recessive inherited
  GPI-deficiency disorder (GPIBD) that clinically overlaps DOORS syndrome, with global
  developmental delay, impaired intellectual development, seizures, and nail/terminal
  phalanx hypoplasia.
alternative_products:
- name: '1'
  id: Q07326-1
- name: '2'
  id: Q07326-2
  sequence_note: VSP_004361
existing_annotations:
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetically inferred localization of PIGF to the ER membrane, where
      the GPI-anchor biosynthetic machinery resides. This is consistent with the direct
      biochemistry and with UniProt's subcellular location assignment.
    action: ACCEPT
    reason: PIGF is a multi-pass ER membrane protein that acts within the ER-localized
      GPI EtNP-transferase complexes; the IBA localization is well supported and represents
      a core aspect of the protein's biology.
    supported_by:
    - reference_id: PMID:32156170
      supporting_text: The core GPI is assembled on the endoplasmic reticulum (ER)
        membrane and is transferred en bloc to the precursor proteins immediately
        after their ER translocation
    - reference_id: file:human/PIGF/PIGF-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetically inferred involvement of PIGF in GPI-anchor biosynthesis.
      PIGF is required for the two late EtNP-transfer steps of the pathway by stabilizing
      the catalytic transferases PIGO and PIGG.
    action: ACCEPT
    reason: This is the core biological process of PIGF and is directly supported by
      experimental characterization of the human protein and its complexes; the IBA
      call is at the correct level of specificity.
    supported_by:
    - reference_id: PMID:32156170
      supporting_text: Two EtNPs are sequentially transferred to the 6-positions of
        Man3 and then Man2 by PIGO
    - reference_id: PMID:32156170
      supporting_text: Both PIGO and PIGG are stabilized by association with PIGF
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic annotation of ER membrane localization, transferred from the
      mouse ortholog (O09101), Ensembl compara, InterPro (IPR009580, the Pig-F family
      domain) and UniProt-SubCell. Concordant with the IBA/ISS/TAS ER-membrane calls.
    action: ACCEPT
    reason: Correct localization for a multi-pass ER membrane protein of the GPI-biosynthetic
      machinery; the electronic mapping agrees with the experimentally supported location.
    supported_by:
    - reference_id: file:human/PIGF/PIGF-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Electronic annotation of GPI-anchor biosynthesis involvement, transferred
      from the mouse ortholog, InterPro (IPR009580) and UniPathway (UPA00196, GPI-anchor
      biosynthesis). Agrees with the core function established experimentally.
    action: ACCEPT
    reason: The InterPro/UniPathway mapping to GPI-anchor biosynthesis is biologically
      correct and matches the experimentally supported role of PIGF.
    supported_by:
    - reference_id: file:human/PIGF/PIGF-uniprot.txt
      supporting_text: glycosylphosphatidylinositol-anchor biosynthesis
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: High-throughput binary (yeast two-hybrid) interaction from the HuRI human
      interactome map. The recorded partners here (AQP6, GPR152, LYVE1, MANBAL, TIMMDC1,
      TMEM130, TMEM14B, TMEM86B) are largely unrelated membrane proteins rather than
      the functionally relevant PIGO/PIGG partners, and 'protein binding' is an uninformative
      molecular-function term.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare 'protein binding' (GO:0005515) conveys no specific molecular function,
      and these are systematic Y2H hits (a screen of the whole interactome, not a PIGF-focused
      study) to unrelated membrane proteins; per curation policy this IPI is retained
      but flagged as over-annotation rather than removed. The functionally meaningful
      interactions of PIGF are with PIGO and PIGG (captured in the process annotations
      and core_functions).
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: we present a human 'all-by-all' reference interactome map of
        human binary protein interactions, or 'HuRI'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:32156170
  qualifier: located_in
  review:
    summary: Author-stated ER-membrane localization (ComplexPortal annotation citing
      the Kinoshita 2020 GPI-biosynthesis review), reflecting that GPI biosynthesis
      including the PIGF-containing EtNP-transferase complexes occurs on the ER membrane.
    action: ACCEPT
    reason: Correct and well-supported localization; consistent with all other ER-membrane
      annotations for this protein.
    supported_by:
    - reference_id: PMID:32156170
      supporting_text: The core GPI is assembled on the endoplasmic reticulum (ER)
        membrane and is transferred en bloc to the precursor proteins immediately
        after their ER translocation
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:33386993
  qualifier: involved_in
  review:
    summary: Experimental (mutant phenotype) evidence that PIGF is required for GPI-anchor
      biosynthesis. A homozygous PIGF missense variant (p.Pro172Arg) in patients with
      a DOORS-syndrome-overlapping phenotype caused defective GPI biosynthesis demonstrated
      by flow cytometry.
    action: ACCEPT
    reason: Direct human loss-of-function evidence firmly places PIGF in GPI-anchor
      biosynthesis and links its deficiency to an inherited GPI-deficiency disorder;
      this is a core annotation.
    supported_by:
    - reference_id: PMID:33386993
      supporting_text: We demonstrate impaired glycosylphosphatidylinositol (GPI) biosynthesis
        through flow cytometry analysis.
    - reference_id: PMID:33386993
      supporting_text: We thus describe the causal role of a novel disease gene, PIGF,
        in DOORS syndrome and highlight the overlap between this condition and GPI
        deficiency disorders.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162742
  qualifier: located_in
  review:
    summary: Reactome traceable-author-statement placing PIGF (as part of the EtNP-transfer
      reaction converting the H6/H7 intermediate to H8) at the ER membrane.
    action: ACCEPT
    reason: Consistent with the established ER-membrane localization of the GPI-biosynthetic
      machinery; correct localization annotation.
    supported_by:
    - reference_id: PMID:32156170
      supporting_text: The core GPI is assembled on the endoplasmic reticulum (ER)
        membrane and is transferred en bloc to the precursor proteins immediately
        after their ER translocation
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity-based (ISS) transfer of ER-membrane localization from
      the mouse ortholog (O09101). Concordant with the direct human evidence.
    action: ACCEPT
    reason: Correct localization; the ortholog-based inference matches the experimentally
      supported ER-membrane location of PIGF.
    supported_by:
    - reference_id: file:human/PIGF/PIGF-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: Sequence-similarity-based (ISS) transfer of GPI-anchor biosynthesis involvement
      from the mouse ortholog (O09101). Matches the experimentally established core
      function.
    action: ACCEPT
    reason: The ortholog-based inference is biologically correct; PIGF's core process
      is GPI-anchor biosynthesis.
    supported_by:
    - reference_id: file:human/PIGF/PIGF-uniprot.txt
      supporting_text: glycosylphosphatidylinositol-anchor biosynthesis
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: TAS
  original_reference_id: PMID:8463218
  qualifier: involved_in
  review:
    summary: Traceable author statement from the original cloning of human PIG-F, which
      identified it as a component of GPI-anchor biosynthesis functioning at the step
      of EtNP transfer to the GPI intermediate bearing three mannoses (i.e. the PIGO-mediated
      EtNP transfer to the third mannose).
    action: ACCEPT
    reason: This is the foundational identification of PIGF as a GPI-anchor biosynthesis
      component; the process annotation is core and correct.
    supported_by:
    - reference_id: PMID:8463218
      supporting_text: PIG-F takes a part in the step of transfer of ethanolamine
        phosphate to the GPI intermediate containing three residues of mannose.
core_functions:
- description: Non-catalytic accessory (stabilizing) subunit required for the activity
    of the GPI ethanolamine-phosphate transferases PIGO and PIGG; participates in the
    late (EtNP-transfer) steps of GPI-anchor biosynthesis in the ER membrane.
  directly_involved_in:
  - id: GO:0006506
    label: GPI anchor biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:15632136
    supporting_text: which is known to bind to and stabilize
  - reference_id: PMID:32156170
    supporting_text: Both PIGO and PIGG are stabilized by association with PIGF
references:
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:8463218
  title: Cloning of a human gene, PIG-F, a component of glycosylphosphatidylinositol
    anchor biosynthesis, by a novel expression cloning strategy.
  findings:
  - statement: Original expression cloning of human PIG-F, identified as a GPI-anchor
      biosynthesis component acting at the EtNP-transfer step on the three-mannose
      GPI intermediate.
    supporting_text: PIG-F takes a part in the step of transfer of ethanolamine phosphate
      to the GPI intermediate containing three residues of mannose.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Foundational cloning paper; abstract-only cache but supports the
      GPI-biosynthesis process annotation.
- id: PMID:15632136
  title: GPI7 is the second partner of PIG-F and involved in modification of glycosylphosphatidylinositol.
  findings:
  - statement: hGPI7 (PIGG) forms a complex with and is stabilized by PIG-F, which
      also binds and stabilizes PIG-O; PIGO and PIGG compete for the shared PIG-F stabilizer.
    supporting_text: hGPI7 was associated with and stabilized by PIG-F, which is known
      to bind to and stabilize PIG-O, a protein homologous to hGPI7.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Directly establishes PIGF as the shared stabilizing subunit of PIGO
      and PIGG; abstract-only cache but the key mechanistic claim is in the abstract.
- id: PMID:32156170
  title: Biosynthesis and biology of mammalian GPI-anchored proteins.
  findings:
  - statement: PIGO and PIGG are the catalytic EtNP transferases (to Man3 and Man2
      respectively) and both are stabilized by association with PIGF; GPI biosynthesis
      occurs on the ER membrane.
    supporting_text: Both PIGO and PIGG are stabilized by association with PIGF
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Authoritative review (full text available) that lays out the pathway
      and PIGF's accessory role and ER localization.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings:
  - statement: Source of the HuRI high-throughput binary (Y2H) interaction dataset
      from which the PIGF 'protein binding' IPI annotations to unrelated membrane proteins
      derive.
    supporting_text: we present a human 'all-by-all' reference interactome map of human
      binary protein interactions, or 'HuRI'
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Large-scale interactome screen; the PIGF hits are uninformative 'protein
      binding' partners unrelated to its GPI-biosynthesis function.
- id: PMID:33386993
  title: PIGF deficiency causes a phenotype overlapping with DOORS syndrome.
  findings:
  - statement: A homozygous PIGF missense variant (p.Pro172Arg) causes impaired GPI
      biosynthesis (shown by flow cytometry) and a DOORS-syndrome-overlapping inherited
      GPI-deficiency phenotype.
    supporting_text: We demonstrate impaired glycosylphosphatidylinositol (GPI) biosynthesis
      through flow cytometry analysis.
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Human loss-of-function evidence linking PIGF to GPI-anchor biosynthesis
      and to an inherited GPI-deficiency disorder (OORS/DOORS-overlap).
- id: Reactome:R-HSA-162742
  title: (ethanolamineP) mannose (a1-2) mannose (a1-6) (ethanolamineP) mannose (a1-4)
    glucosaminyl-acyl-PI -> (ethanolamineP) mannose (a1-2) (ethanolamineP) mannose
    (a1-6) (ethanolamineP) mannose (a1-4) glucosaminyl-acyl-PI
  findings: []
- id: file:human/PIGF/PIGF-uniprot.txt
  title: UniProt entry Q07326 (PIGF_HUMAN)
  findings:
  - statement: UniProt describes PIGF as the stabilizing subunit of the EtNP transferase
      2 and 3 complexes (with PIGG and PIGO), an ER membrane multi-pass protein, required
      to stabilize PIGG and PIGO.
    supporting_text: Stabilizing subunit of the ethanolamine phosphate transferase
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Curated UniProt record used for localization, subunit/complex, and
      pathway statements.