id: Q5H8A4
gene_symbol: PIGG
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: PIGG is the catalytic subunit of the glycosylphosphatidylinositol (GPI)
  ethanolamine phosphate transferase II complex (GPI-ET-II; also known as GPI7/hGPI7).
  During GPI-anchor biosynthesis in the endoplasmic reticulum, PIGG transfers an ethanolamine
  phosphate (EtNP), donated by phosphatidylethanolamine, onto the 6-OH of the second
  alpha-1,6-linked mannose of the GPI intermediate (the H7-to-H8 conversion). This
  second-mannose EtNP is a side-branch modification that is normally removed shortly
  after the anchor is transferred to protein. PIGG acts together with the accessory
  subunit PIGF, which stabilizes it, and competes with PIGO (which adds EtNP to the
  third mannose) for the shared PIGF stabilizer. PIGG is a multi-pass endoplasmic reticulum
  membrane protein with a large lumenal alkaline-phosphatase-like catalytic domain.
  Biallelic loss-of-function variants cause an inherited GPI-deficiency disorder characterized
  by intellectual disability/developmental delay, early-onset seizures, hypotonia, and
  cerebellar atrophy; genetic variation in PIGG also defines the Emm blood group system.
alternative_products:
- name: '1'
  id: Q5H8A4-1
- name: '2'
  id: Q5H8A4-2
  sequence_note: VSP_019832
- name: '3'
  id: Q5H8A4-3
  sequence_note: VSP_019828
- name: '4'
  id: Q5H8A4-4
  sequence_note: VSP_019831, VSP_019833
- name: '5'
  id: Q5H8A4-5
  sequence_note: VSP_019827, VSP_019829, VSP_019830
- name: '6'
  id: Q5H8A4-6
  sequence_note: VSP_054387, VSP_054388, VSP_019833
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: PIGG is a multi-pass endoplasmic reticulum membrane protein and carries
      out its EtNP-transferase reaction in the ER during GPI-anchor biosynthesis.
      The phylogenetic (IBA) location call is consistent with direct experimental
      localization and with the UniProt subcellular location.
    action: ACCEPT
    reason: Correct compartment for the site of PIGG action, corroborated by experimental
      localization (PMID:15632136) and UniProt.
    supported_by:
    - reference_id: file:human/PIGG/PIGG-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0051377
    label: mannose-ethanolamine phosphotransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: This is the core molecular function of PIGG - transfer of ethanolamine
      phosphate from phosphatidylethanolamine to the second mannose of the GPI intermediate.
      The IBA call at this term is well supported by the human experimental data and
      the conserved yeast ortholog Gpi7p.
    action: ACCEPT
    reason: Represents the correct, specific catalytic activity of PIGG and is the
      core function; matches the current GOA term.
    supported_by:
    - reference_id: PMID:32156170
      supporting_text: PIGG (initially termed GPI7) [67], catalytic subunits of GPI-ETII
        and GPI-ETIII. Both PIGO and PIGG are stabilized by association with PIGF
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: PIGG catalyzes one step (transfer of EtNP to the second mannose) of the
      glycosylphosphatidylinositol-anchor biosynthetic pathway. The IBA process call
      is well supported.
    action: ACCEPT
    reason: Correct core biological process for this GPI-anchor biosynthetic enzyme.
    supported_by:
    - reference_id: PMID:34113002
      supporting_text: is an ethanolamine phosphate transferase that catalyzes the
        modification of the second mannose of glycosylphosphatidylinositol (GPI)
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic mapping from the UniProt subcellular location vocabulary (SL-0097,
      ER membrane), consistent with experimental localization of PIGG.
    action: ACCEPT
    reason: Correct location, agrees with experimental evidence and UniProt curation.
    supported_by:
    - reference_id: file:human/PIGG/PIGG-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: 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: Automated inference (InterPro/UniPathway) that PIGG participates in GPI-anchor
      biosynthesis. This is correct and consistent with experimental data.
    action: ACCEPT
    reason: Correct process; the InterPro/UniPathway mapping is sound for this GPI-ET
      family enzyme.
    supported_by:
    - reference_id: file:human/PIGG/PIGG-uniprot.txt
      supporting_text: 'PATHWAY: Glycolipid biosynthesis; glycosylphosphatidylinositol-anchor'
- term:
    id: GO:0051377
    label: mannose-ethanolamine phosphotransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based electronic assignment of the specific mannose-ethanolamine
      phosphotransferase activity, matching the experimentally established function.
    action: ACCEPT
    reason: Correct specific molecular function; the InterPro2GO mapping is appropriate.
    supported_by:
    - reference_id: PMID:15632136
      supporting_text: forms a protein complex with PIG-F and is involved in the H7-to-H8
        conversion
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23864651
  qualifier: enables
  review:
    summary: An IntAct-derived interaction annotation linking PIGG to the GLP-1 receptor
      (GLP1R, P43220), from a study screening for novel GLP1R interactors. Bare "protein
      binding" is uninformative and this interaction is not part of PIGG's characterized
      catalytic function in GPI-anchor biosynthesis; there is no evidence it reflects
      a physiological binding activity of PIGG.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative generic "protein binding" from a high-throughput interactome
      screen; per curation guidelines this term does not convey PIGG's actual molecular
      function and the GLP1R interaction is not an established functional partner.
    supported_by:
    - reference_id: file:human/PIGG/PIGG-uniprot.txt
      supporting_text: 'Q5H8A4; P43220: GLP1R; NbExp=2; IntAct=EBI-11724298, EBI-7466542'
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162710
  qualifier: involved_in
  review:
    summary: Reactome traceable assertion that PIGG participates in synthesis of GPI.
      Correct and consistent with the experimental and phylogenetic evidence.
    action: ACCEPT
    reason: Correct core process from an authoritative pathway resource.
    supported_by:
    - reference_id: PMID:32156170
      supporting_text: PIGG (initially termed GPI7) [67], catalytic subunits of GPI-ETII
        and GPI-ETIII. Both PIGO and PIGG are stabilized by association with PIGF
- term:
    id: GO:0051377
    label: mannose-ethanolamine phosphotransferase activity
  evidence_type: IDA
  original_reference_id: PMID:15632136
  qualifier: enables
  review:
    summary: Direct experimental evidence (Shishioh et al. 2005) that human GPI7/PIGG,
      in complex with PIG-F, mediates the transfer of ethanolamine phosphate to the
      second mannose (H7-to-H8 conversion). This is the defining catalytic activity
      of PIGG.
    action: ACCEPT
    reason: Experimentally demonstrated core molecular function; matches the current
      GOA term (GO:0051377; the older UniProt-DR term GO:0051267 is now obsolete).
    supported_by:
    - reference_id: PMID:15632136
      supporting_text: an additional ethanolamine phosphate (EtNP) to the second mannose
    - reference_id: PMID:15632136
      supporting_text: forms a protein complex with PIG-F and is involved in the H7-to-H8
        conversion
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:15632136
  qualifier: located_in
  review:
    summary: Experimental localization of PIGG/hGPI7 to the endoplasmic reticulum
      membrane, where GPI-anchor biosynthesis occurs.
    action: ACCEPT
    reason: Experimentally supported correct location of action.
    supported_by:
    - reference_id: file:human/PIGG/PIGG-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:32156170
  qualifier: located_in
  review:
    summary: Author-statement (review) localization to the ER membrane, consistent
      with the described role of PIGG as a multi-pass ER-membrane GPI-ET enzyme.
    action: ACCEPT
    reason: Correct location; consistent with experimental data and the ComplexPortal
      GPI-ETII complex annotation.
    supported_by:
    - reference_id: PMID:32156170
      supporting_text: Three GPI-ETs (PIGN, PIGO and PIGG) are also multiple transmembrane
        proteins bearing catalytic sites within the luminal regions
- term:
    id: GO:0016740
    label: transferase activity
  evidence_type: IMP
  original_reference_id: PMID:34113002
  qualifier: enables
  review:
    summary: The variant-pathogenicity study measured PIGG enzymatic (EtNP-transferase)
      activity via restoration of GPI-AP expression in PIGO/PIGG double-knockout cells,
      showing that pathogenic variants abolish or reduce this activity. The generic
      parent "transferase activity" understates the specific, experimentally assayed
      function.
    action: MODIFY
    reason: Too general; the assay specifically measures PIGG's ethanolamine-phosphate
      transferase (mannose-ethanolamine phosphotransferase) activity, so it should
      be replaced by the specific molecular function term.
    proposed_replacement_terms:
    - id: GO:0051377
      label: mannose-ethanolamine phosphotransferase activity
    supported_by:
    - reference_id: PMID:34113002
      supporting_text: ten variants had a null enzymatic activity
    - reference_id: PMID:34113002
      supporting_text: is an ethanolamine phosphate transferase that catalyzes the
        modification of the second mannose of glycosylphosphatidylinositol (GPI)
- term:
    id: GO:0016780
    label: phosphotransferase activity, for other substituted phosphate groups
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162742
  qualifier: enables
  review:
    summary: Reactome traceable assertion capturing PIGG's phosphotransferase (EtNP-transfer)
      reaction at a broader level. This is a correct parent of the specific mannose-ethanolamine
      phosphotransferase activity but is less informative than GO:0051377.
    action: KEEP_AS_NON_CORE
    reason: Correct but non-core generic parent term from Reactome; the specific EtNP-transferase
      activity (GO:0051377) is the core function captured elsewhere.
    supported_by:
    - reference_id: PMID:15632136
      supporting_text: an additional ethanolamine phosphate (EtNP) to the second mannose
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput mass-spectrometry detection of PIGG in an NK-cell membrane
      proteome. "Membrane" is an uninformative parent term; the specific and correct
      location for PIGG is the endoplasmic reticulum membrane.
    action: MARK_AS_OVER_ANNOTATED
    reason: Uninformative high-level compartment from a bulk membrane-proteome study;
      the specific ER membrane term is better supported and captured by other annotations.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: approximately 40% of the identified proteins were predicted
        as plausible membrane proteins
- 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 assertion placing PIGG's reaction at the ER membrane,
      consistent with all other localization evidence.
    action: ACCEPT
    reason: Correct location from an authoritative pathway resource.
    supported_by:
    - reference_id: file:human/PIGG/PIGG-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:15632136
  qualifier: located_in
  review:
    summary: Direct experimental localization of PIGG/hGPI7 to the endoplasmic reticulum
      (broader compartment consistent with the ER membrane annotations).
    action: ACCEPT
    reason: Correct compartment, experimentally supported; a valid broader parent
      of endoplasmic reticulum membrane.
    supported_by:
    - reference_id: file:human/PIGG/PIGG-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:15632136
  qualifier: acts_upstream_of_or_within
  review:
    summary: Direct experimental evidence that knockdown of hGPI7/PIGG blocks the
      H7-to-H8 conversion, placing PIGG within the GPI-anchor biosynthetic process.
    action: ACCEPT
    reason: Experimentally supported involvement in the core GPI-anchor biosynthetic
      process.
    supported_by:
    - reference_id: PMID:15632136
      supporting_text: forms a protein complex with PIG-F and is involved in the H7-to-H8
        conversion
core_functions:
- description: Catalytic subunit of the GPI ethanolamine phosphate transferase II
    complex that transfers ethanolamine phosphate (from phosphatidylethanolamine)
    onto the second mannose of the GPI intermediate during GPI-anchor biosynthesis
    in the ER, acting together with the stabilizing subunit PIGF.
  molecular_function:
    id: GO:0051377
    label: mannose-ethanolamine phosphotransferase activity
  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: forms a protein complex with PIG-F and is involved in the H7-to-H8
      conversion
  - reference_id: PMID:34113002
    supporting_text: is an ethanolamine phosphate transferase that catalyzes the modification
      of the second mannose of glycosylphosphatidylinositol (GPI)
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:15632136
  title: GPI7 is the second partner of PIG-F and involved in modification of glycosylphosphatidylinositol.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Primary paper establishing that human GPI7/PIGG forms a complex with
      PIG-F and mediates EtNP transfer to the second mannose (H7-to-H8 conversion);
      abstract cached (full text not available). Supports the core MF, BP, and ER
      location.
- id: PMID:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput NK-cell membrane proteome MS study; only supports
      a generic "membrane" localization for PIGG, not an informative function.
- id: PMID:23864651
  title: The identification of novel proteins that interact with the GLP-1 receptor
    and restrain its activity.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Source of the IntAct PIGG-GLP1R interaction (bare protein binding).
      The paper is a GLP1R interactome screen and does not establish a physiological
      binding function for PIGG; annotation marked as over-annotated.
- id: PMID:32156170
  title: Biosynthesis and biology of mammalian GPI-anchored proteins.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Authoritative review placing PIGG (GPI7) as the catalytic subunit
      of GPI-ETII adding EtNP to the second mannose, stabilized by PIGF; supports
      function, complex, ER localization, and disease (IGD).
- id: PMID:34113002
  title: PIGG variant pathogenicity assessment reveals characteristic features within
    19 families.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full-text (PMC9900493) study of 19 families with biallelic PIGG
      variants; functional assay of EtNP-transferase activity in PIGO/PIGG DKO cells
      and detailed neurodevelopmental phenotype (DD/ID, seizures, hypotonia, cerebellar
      atrophy). Supports the IMP MF, BP, and disease.
- id: Reactome:R-HSA-162710
  title: Synthesis of glycosylphosphatidylinositol (GPI)
  findings: []
- 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: []