id: Q8TEQ8
gene_symbol: PIGO
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: PIGO is the catalytic subunit of the GPI ethanolamine phosphate transferase
  3 complex (GPI-ET-III), an endoplasmic reticulum membrane multi-pass enzyme in the
  glycosylphosphatidylinositol (GPI) anchor biosynthetic pathway. It transfers a bridging
  ethanolamine phosphate (EtNP), derived from phosphatidylethanolamine, onto the 6-OH
  of the third mannose of the GPI intermediate; this is the EtNP through which the
  mature protein's C-terminus is ultimately joined to the anchor by the GPI transamidase.
  PIGO functions together with the accessory subunit PIGF, which is required to stabilise
  it, and it catalyses the tenth step of the eleven-step core GPI assembly on the ER
  membrane. Biallelic loss-of-function of PIGO causes hyperphosphatasia with impaired
  intellectual development syndrome 2 (HPMRS2 / Mabry syndrome), characterised by
  developmental delay, seizures, brachytelephalangy, and elevated serum alkaline
  phosphatase.
alternative_products:
- name: '1'
  id: Q8TEQ8-1
- name: '2'
  id: Q8TEQ8-2
  sequence_note: VSP_003944
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: PIGO acts as a multi-pass ER membrane enzyme; the core GPI is assembled
      on the ER membrane. IBA localization is consistent with UniProt (ISS from mouse
      ortholog) and the pathway literature.
    action: ACCEPT
    reason: The phylogenetically inferred ER membrane localization matches the experimental
      and homology-based evidence and the known site of GPI biosynthesis.
    supported_by:
    - reference_id: PMID:32156170
      supporting_text: The core GPI is assembled on the endoplasmic reticulum (ER)
        membrane
    - reference_id: file:human/PIGO/PIGO-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: PIGO catalyses step 10 of the eleven core reactions of GPI-anchor biosynthesis,
      transferring the bridging ethanolamine phosphate to the third mannose. Core biological
      process for this gene.
    action: ACCEPT
    reason: Directly supported by the biosynthetic role established in the literature
      and UniProt pathway annotation.
    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: file:human/PIGO/PIGO-uniprot.txt
      supporting_text: participates in the tenth step of the glycosylphosphatidylinositol-
- 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 precise molecular function of PIGO (GPI-ET-III) - transfer
      of ethanolamine phosphate to a mannose residue of the GPI lipid precursor (the
      third mannose). Represents the core catalytic activity of the gene.
    action: ACCEPT
    reason: GO:0051377 is defined as catalysis of transfer of ethanolamine phosphate
      to a mannose residue in the GPI lipid precursor, exactly matching PIGO's characterized
      reaction; the IBA is concordant with UniProt (IMP) and the pathway literature.
    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: file:human/PIGO/PIGO-uniprot.txt
      supporting_text: transfers an ethanolamine phosphate (EtNP) from a
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UniProt SubCellular Location mapping to ER membrane; consistent with the
      multi-pass ER membrane topology and the ER site of GPI assembly.
    action: ACCEPT
    reason: Correct localization; concordant with the IBA, ISS and NAS ER membrane
      annotations.
    supported_by:
    - reference_id: file:human/PIGO/PIGO-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: Automated (ARBA/InterPro/UniPathway) assignment to GPI-anchor biosynthesis,
      matching PIGO's role in the core GPI assembly pathway.
    action: ACCEPT
    reason: Correct core process; agrees with experimental (IMP) and phylogenetic (IBA)
      annotations to the same term.
    supported_by:
    - reference_id: file:human/PIGO/PIGO-uniprot.txt
      supporting_text: participates in the tenth step of the glycosylphosphatidylinositol-
- term:
    id: GO:0016772
    label: transferase activity, transferring phosphorus-containing groups
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro2GO mapping to a very high-level transferase parent term. Not wrong
      (PIGO does transfer a phosphorus-containing EtNP group), but far less informative
      than the specific GO:0051377 that is already annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0016772 is a broad ancestor of the specific molecular function GO:0051377
      (mannose-ethanolamine phosphotransferase activity) already captured; the specific
      term should represent the molecular function, so the generic parent is redundant/over-general.
    supported_by:
    - reference_id: file:human/PIGO/PIGO-uniprot.txt
      supporting_text: transfers an ethanolamine phosphate (EtNP) from a
- term:
    id: GO:0051377
    label: mannose-ethanolamine phosphotransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Automated (ARBA/InterPro) assignment of the correct specific molecular
      function of PIGO.
    action: ACCEPT
    reason: Matches PIGO's characterized catalytic activity and the IBA/IMP annotations
      to the same term.
    supported_by:
    - reference_id: file:human/PIGO/PIGO-uniprot.txt
      supporting_text: transfers an ethanolamine phosphate (EtNP) from a
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: ER membrane localization transferred by sequence similarity from the mouse
      ortholog (UniProtKB:Q9JJI6). Consistent with all other localization evidence.
    action: ACCEPT
    reason: Correct localization supported by ortholog data and the ER site of GPI
      biosynthesis.
    supported_by:
    - reference_id: file:human/PIGO/PIGO-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:24417746
  qualifier: involved_in
  review:
    summary: Patient PIGO mutations (compound heterozygous, including T130N) cause GPI
      deficiency with reduced cell-surface GPI-anchored proteins, demonstrating PIGO's
      involvement in GPI-anchor biosynthesis. The T130N variant decreases mannose-ethanolamine
      phosphotransferase activity.
    action: ACCEPT
    reason: Loss-of-function variants impairing GPI-AP expression establish PIGO's role
      in the GPI-anchor biosynthetic process; corroborated by UniProt variant/functional
      annotation.
    supported_by:
    - reference_id: PMID:24417746
      supporting_text: Our findings therefore expand the clinical spectrum of
    - reference_id: file:human/PIGO/PIGO-uniprot.txt
      supporting_text: decrease in mannose-ethanolamine
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:28337824
  qualifier: involved_in
  review:
    summary: Genotype-phenotype study of PIGO deficiency using a PIGO-deficient cell
      line and functional assays; multiple patient variants reduce activity and GPI-AP
      surface expression, confirming PIGO's role in GPI-anchor biosynthesis.
    action: ACCEPT
    reason: Functional analyses in a PIGO-deficient cell line link PIGO loss to defective
      GPI biosynthesis; concordant with UniProt catalytic/variant annotation.
    supported_by:
    - reference_id: PMID:28337824
      supporting_text: PIGO deficiency shows characteristic features, such as Hirschsprung
        disease,
    - reference_id: file:human/PIGO/PIGO-uniprot.txt
      supporting_text: decrease in mannose-ethanolamine
- term:
    id: GO:0051377
    label: mannose-ethanolamine phosphotransferase activity
  evidence_type: IMP
  original_reference_id: PMID:24417746
  qualifier: enables
  review:
    summary: The PIGO T130N patient variant decreases mannose-ethanolamine phosphotransferase
      activity, providing experimental (mutation) support that PIGO enables this molecular
      function.
    action: ACCEPT
    reason: Variant-based functional evidence for PIGO's characterized catalytic activity
      (transfer of EtNP to the GPI mannose); the enzyme is the source (ECO:0000305) of
      the UniProt catalytic-activity annotation.
    supported_by:
    - reference_id: file:human/PIGO/PIGO-uniprot.txt
      supporting_text: decrease in mannose-ethanolamine
    - reference_id: PMID:24417746
      supporting_text: Our findings therefore expand the clinical spectrum of
- term:
    id: GO:0051377
    label: mannose-ethanolamine phosphotransferase activity
  evidence_type: IMP
  original_reference_id: PMID:28337824
  qualifier: enables
  review:
    summary: Functional analysis of multiple HPMRS2 PIGO variants (e.g. R119W, M344K,
      N370S, K1047E) in a PIGO-deficient cell line shows decreased mannose-ethanolamine
      phosphotransferase activity, supporting PIGO's catalytic function.
    action: ACCEPT
    reason: Directed mutagenesis / patient-variant activity assays demonstrate PIGO
      enables the specific EtNP-transferase activity; concordant with UniProt.
    supported_by:
    - reference_id: file:human/PIGO/PIGO-uniprot.txt
      supporting_text: decrease in mannose-ethanolamine
    - reference_id: PMID:28337824
      supporting_text: functional analysis
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:24049131
  qualifier: involved_in
  review:
    summary: Inherited GPI deficiency due to PIGO mutation (R119W), presenting as vitamin
      B6-responsive epilepsy; loss of PIGO function impairs GPI-anchor biosynthesis.
    action: ACCEPT
    reason: Patient loss-of-function evidence establishes PIGO's involvement in the
      GPI-anchor biosynthetic process; the R119W variant decreases EtNP-transferase
      activity per UniProt.
    supported_by:
    - reference_id: PMID:24049131
      supporting_text: Vitamin B6-responsive epilepsy due to inherited GPI deficiency
    - reference_id: file:human/PIGO/PIGO-uniprot.txt
      supporting_text: decrease in mannose-ethanolamine
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:32156170
  qualifier: located_in
  review:
    summary: The GPI biosynthesis review (basis for ComplexPortal CPX-2679) places core
      GPI assembly, including the PIGO/PIGF EtNP-transferase III complex, on the ER
      membrane.
    action: ACCEPT
    reason: Author statement consistent with all other ER membrane evidence and the
      known site of GPI assembly.
    supported_by:
    - reference_id: PMID:32156170
      supporting_text: The core GPI is assembled on the endoplasmic reticulum (ER)
        membrane
- term:
    id: GO:0051377
    label: mannose-ethanolamine phosphotransferase activity
  evidence_type: IMP
  original_reference_id: PMID:24049131
  qualifier: enables
  review:
    summary: The PIGO R119W patient variant decreases mannose-ethanolamine phosphotransferase
      activity, supporting that PIGO enables this molecular function.
    action: ACCEPT
    reason: Variant functional evidence for PIGO's specific catalytic activity; concordant
      with UniProt catalytic-activity annotation (ECO:0000305 from this paper).
    supported_by:
    - reference_id: file:human/PIGO/PIGO-uniprot.txt
      supporting_text: decrease in mannose-ethanolamine
    - reference_id: PMID:24049131
      supporting_text: Vitamin B6-responsive epilepsy due to inherited GPI deficiency
- term:
    id: GO:0016020
    label: membrane
  evidence_type: HDA
  original_reference_id: PMID:19946888
  qualifier: located_in
  review:
    summary: High-throughput MS identification of PIGO in the NK-cell (YTS) membrane
      proteome. Correct that PIGO is a membrane protein, but "membrane" is an uninformative
      generic parent of the specific ER membrane localization already annotated.
    action: MARK_AS_OVER_ANNOTATED
    reason: GO:0016020 is a high-level ancestor of GO:0005789 (endoplasmic reticulum
      membrane); the specific ER membrane term better represents PIGO's localization,
      and the proteomics hit does not distinguish sub-membrane compartment.
    supported_by:
    - reference_id: PMID:19946888
      supporting_text: approximately 40% of the identified proteins were predicted as
        plausible membrane proteins
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: GPI-anchor biosynthesis role transferred by sequence similarity from the
      mouse ortholog (UniProtKB:Q9JJI6). Core process for PIGO.
    action: ACCEPT
    reason: Correct core biological process; concordant with experimental (IMP), automated
      (IEA) and phylogenetic (IBA) annotations to the same term.
    supported_by:
    - reference_id: file:human/PIGO/PIGO-uniprot.txt
      supporting_text: participates in the tenth step of the glycosylphosphatidylinositol-
core_functions:
- description: Catalytic subunit of GPI ethanolamine phosphate transferase III (GPI-ET-III);
    transfers the bridging ethanolamine phosphate from phosphatidylethanolamine onto
    the third mannose of the GPI intermediate (the protein-attachment EtNP), acting
    with the accessory 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:32156170
    supporting_text: Two EtNPs are sequentially transferred to the 6-positions of Man3
      and then Man2 by PIGO
  - reference_id: file:human/PIGO/PIGO-uniprot.txt
    supporting_text: transfers an ethanolamine phosphate (EtNP) from a
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- 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: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:19946888
  title: Defining the membrane proteome of NK cells.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Proteomics MS identification of PIGO in an NK-cell membrane fraction;
      supports only generic membrane localization, not a specific function.
- id: PMID:24049131
  title: Vitamin B6-responsive epilepsy due to inherited GPI deficiency.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Reports a PIGO (R119W) patient with inherited GPI deficiency and
      characterizes decreased EtNP-transferase activity; abstract-only in cache but
      UniProt cites it for FUNCTION/CATALYTIC ACTIVITY and the R119W variant effect.
- id: PMID:24417746
  title: PIGO mutations in intractable epilepsy and severe developmental delay with
    mild elevation of alkaline phosphatase levels.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Compound-heterozygous PIGO patients (T130N/Q430*) with decreased
      GPI-AP surface expression; UniProt attributes the T130N activity decrease to
      this paper.
- id: PMID:28337824
  title: Phenotype-genotype correlations of PIGO deficiency with variable phenotypes
    from infantile lethality to mild learning difficulties.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Functional analysis of multiple PIGO variants in a PIGO-deficient
      cell line; establishes decreased EtNP-transferase activity and links to GPI-AP
      deficiency.
- id: PMID:32156170
  title: Biosynthesis and biology of mammalian GPI-anchored proteins.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Authoritative review; Table 2 lists PIGO at step 10 as GPI-ETIII
      catalytic, PIGF as regulatory; describes EtNP transfer to Man3 and ER assembly
      site.
- id: file:human/PIGO/PIGO-uniprot.txt
  title: UniProtKB entry Q8TEQ8 (PIGO_HUMAN), GPI ethanolamine phosphate transferase
    3, catalytic subunit
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Source of function, catalytic activity, pathway, subunit (PIGF),
      subcellular location, and variant functional data used throughout this review.