id: Q9NUD9
gene_symbol: PIGV
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: PIGV (GPI alpha-1,6-mannosyltransferase 2; GPI mannosyltransferase II,
  GPI-MT-II) is a multi-pass endoplasmic reticulum membrane protein that catalyzes
  transfer of the second mannose, via an alpha-1,6 linkage, from dolichyl-phosphate-mannose
  (Dol-P-Man) onto the growing glycosylphosphatidylinositol (GPI) intermediate (Man1-GlcN-(acyl)PI
  to Man2-GlcN-(acyl)PI). This is one of four Dol-P-Man-dependent mannosyltransferase
  steps in GPI-anchor biosynthesis, occurring on the lumenal face of the ER membrane;
  the resulting GPI anchor is used to attach many proteins to the cell surface. PIGV
  belongs to CAZy glycosyltransferase family GT76 (Pfam Mannosyl_trans2 / InterPro
  PIG-V/Gpi18) and is conserved across eukaryotes, with the Saccharomyces cerevisiae
  ortholog GPI18/YBR004C. Loss-of-function variants cause hyperphosphatasia with impaired
  intellectual development syndrome 1 (HPMRS1, Mabry syndrome), characterized by elevated
  serum alkaline phosphatase, intellectual disability, seizures, hypotonia, and facial
  dysmorphism.
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: Phylogenetic (IBA) localization of PIGV activity to the ER membrane.
      PIGV is a multi-pass ER membrane enzyme whose GPI-MT-II activity acts on the
      lumenal face of the ER, so ER membrane is the correct site of action. Consistent
      with direct experimental localization (PMID:15623507) and UniProt subcellular
      location.
    action: ACCEPT
    reason: Correct and specific cellular component for this ER-resident GPI biosynthetic
      enzyme; supported by direct experimental evidence in addition to the IBA inference.
    supported_by:
    - reference_id: PMID:15623507
      supporting_text: Human PIG-V encodes a 493-amino acid, endoplasmic reticulum
        (ER) resident protein with eight putative transmembrane regions.
- term:
    id: GO:0120563
    label: dol-P-Man:Man(1)GlcN-acyl-PI alpha-1,6-mannosyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (IBA) assignment of the specific GPI-MT-II catalytic activity,
      the transfer of the second mannose via an alpha-1,6 bond from Dol-P-Man onto
      the Man1-GlcN-(acyl)PI GPI intermediate. This is the exact enzymatic activity
      of PIGV and the most informative molecular function term available; it is corroborated
      by direct human experimental work (PMID:15623507) and yeast/human complementation
      (PMID:15720390).
    action: ACCEPT
    reason: This is the core molecular function of PIGV, at the correct level of specificity.
    supported_by:
    - reference_id: PMID:15623507
      supporting_text: Here we report the cloning of PIG-V involved in transferring
        the second mannose in the GPI anchor.
    - reference_id: PMID:15623507
      supporting_text: four Dol-P-Man-dependent mannosyltransferases, GPI-MT-I, -MT-II,
        -MT-III, and -MT-IV for the first, second, third, and fourth mannoses
- term:
    id: GO:0031501
    label: mannosyltransferase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: Phylogenetic (IBA) assignment of PIGV to a mannosyltransferase complex.
      Mammalian GPI-MT-II activity is attributed to PIG-V acting as the catalyst or
      as a component of the catalytic complex, so complex membership is plausible.
      However, the composition of a distinct PIGV mannosyltransferase complex in human
      is not experimentally well established here, so this is retained as a supporting
      (non-core) annotation rather than a defining function.
    action: KEEP_AS_NON_CORE
    reason: Reasonable at the phylogenetic level and consistent with GPI-MT-II being
      a component of a catalytic assembly, but it is a supporting structural annotation,
      not the core catalytic/process function of the gene.
    supported_by:
    - reference_id: Reactome:R-HSA-162873
      supporting_text: PIG-V was identified as the catylyst, or a component of the
        catalyst, of this reaction
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic (IBA) assignment to GPI anchor biosynthesis. PIGV catalyzes
      the seventh step of the GPI-anchor biosynthetic pathway (second-mannose addition),
      so this is the correct core biological process.
    action: ACCEPT
    reason: Core biological process of PIGV; strongly supported by experimental (PMID:15623507,
      PMID:15720390) and pathway evidence.
    supported_by:
    - reference_id: PMID:15623507
      supporting_text: The biosynthetic pathway of GPI is mediated by sequential additions
        of sugars and other components to phosphatidylinositol.
    - reference_id: PMID:15720390
      supporting_text: A bioinformatics-based strategy identified the essential Saccharomyces
        cerevisiae Ybr004c protein as a candidate for the second GPI alpha-mannosyltransferase
        (GPI-MT-II).
- term:
    id: GO:0000009
    label: alpha-1,6-mannosyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro2GO (IEA) mapping from the PIG-V/Gpi18 domain (IPR007315) to
      alpha-1,6-mannosyltransferase activity. This is a correct but less specific
      parent of the exact PIGV activity (GO:0120563); PIGV forms the alpha-1,6 mannosyl
      linkage.
    action: ACCEPT
    reason: Accurate parent molecular-function term; consistent with the specific
      GPI-MT-II activity but broader. Kept as a correct (non-core) generalization.
    supported_by:
    - reference_id: PMID:15623507
      supporting_text: 'PIG-V involved in transferring the second mannose in glycosylphosphatidylinositol.'
- term:
    id: GO:0004376
    label: GPI mannosyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro2GO (IEA) mapping from the PIG-V/Gpi18 domain (IPR007315) to
      GPI mannosyltransferase activity. This is a correct parent term of the specific
      PIGV activity (GO:0120563 is a subclass of GO:0004376) and accurately describes
      PIGV as a GPI mannosyltransferase.
    action: ACCEPT
    reason: Accurate parent molecular-function term for this GPI mannosyltransferase;
      broader than the specific GPI-MT-II term but correct.
    supported_by:
    - reference_id: PMID:15623507
      supporting_text: four Dol-P-Man-dependent mannosyltransferases, GPI-MT-I, -MT-II,
        -MT-III, and -MT-IV for the first, second, third, and fourth mannoses
- 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 keyword mapping (IEA) to ER membrane, matching
      the experimentally determined localization of PIGV as a multi-pass ER membrane
      protein.
    action: ACCEPT
    reason: Correct localization, consistent with experimental IDA evidence and UniProt.
    supported_by:
    - reference_id: file:human/PIGV/PIGV-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 (IEA) assignment to GPI anchor biosynthesis via InterPro and
      UniPathway (UPA00196). This is the correct core biological process for PIGV.
    action: ACCEPT
    reason: Correct core biological process; independently supported by experimental
      annotations.
    supported_by:
    - reference_id: PMID:15720390
      supporting_text: A bioinformatics-based strategy identified the essential Saccharomyces
        cerevisiae Ybr004c protein as a candidate for the second GPI alpha-mannosyltransferase
        (GPI-MT-II).
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Bare 'protein binding' from a large-scale yeast two-hybrid neurodegenerative-disease
      interactome screen (interactions reported with TGFBR2, CBX5, and SERPINH1).
      The term is uninformative about molecular function and the proposed partners
      are not expected physiological interactors of an ER-lumenal GPI biosynthetic
      enzyme.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding provides no functional insight and derives from a
      high-throughput Y2H screen; per curation policy this is marked as over-annotated
      rather than removed.
    supported_by:
    - reference_id: PMID:32814053
      supporting_text: systematic yeast two-hybrid interaction screening of ∼500 ND-related
        proteins and integration of literature interactions
- 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 (TAS) placement of PIGV in the human GPI synthesis pathway (Synthesis
      of glycosylphosphatidylinositol). Correct core biological process.
    action: ACCEPT
    reason: Correct core biological process, curated from Reactome pathway knowledge.
    supported_by:
    - reference_id: Reactome:R-HSA-162710
      supporting_text: GPI is synthesized in the endoplasmic reticulum.
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA, IDA) localizing PIGV to the endoplasmic
      reticulum. Correct but less specific than the ER membrane annotation; PIGV is
      an integral ER membrane protein.
    action: ACCEPT
    reason: Experimentally supported ER localization; correct parent of the more specific
      ER membrane term. Retained as accurate.
    supported_by:
    - reference_id: PMID:15623507
      supporting_text: Human PIG-V encodes a 493-amino acid, endoplasmic reticulum
        (ER) resident protein with eight putative transmembrane regions.
- term:
    id: GO:0004376
    label: GPI mannosyltransferase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162873
  qualifier: enables
  review:
    summary: Reactome (TAS) assignment of GPI mannosyltransferase activity to PIGV
      for the second-mannose-addition reaction. Correct parent of the specific GPI-MT-II
      activity (GO:0120563).
    action: ACCEPT
    reason: Accurate GPI mannosyltransferase molecular function, curated from Reactome;
      a correct generalization of the specific PIGV activity.
    supported_by:
    - reference_id: Reactome:R-HSA-162873
      supporting_text: a second mannose residue is added to the glycolipid on the
        lumenal face of the endoplasmic reticulum membrane
- term:
    id: GO:0120563
    label: dol-P-Man:Man(1)GlcN-acyl-PI alpha-1,6-mannosyltransferase activity
  evidence_type: IMP
  original_reference_id: PMID:15623507
  qualifier: enables
  review:
    summary: Direct experimental evidence (IMP) that human PIG-V is the second GPI
      mannosyltransferase (GPI-MT-II), transferring the second mannose via an alpha-1,6
      linkage. Kang et al. cloned PIG-V, defined its catalytic activity and ER topology,
      and identified functionally important lumenal residues by mutagenesis. This
      is the exact catalytic activity of PIGV.
    action: ACCEPT
    reason: Core molecular function with direct experimental support at the correct
      specificity.
    supported_by:
    - reference_id: PMID:15623507
      supporting_text: Here we report the cloning of PIG-V involved in transferring
        the second mannose in the GPI anchor.
    - reference_id: PMID:15623507
      supporting_text: PIG-V has two functionally important conserved regions facing
        the ER lumen.
- term:
    id: GO:0120563
    label: dol-P-Man:Man(1)GlcN-acyl-PI alpha-1,6-mannosyltransferase activity
  evidence_type: IGI
  original_reference_id: PMID:15623507
  qualifier: enables
  review:
    summary: Genetic interaction evidence (IGI) supporting the GPI-MT-II activity
      of PIGV, based on functional complementation with the yeast ortholog GPI18/YBR004C
      (UniProtKB:P38211). Human PIG-V cDNA rescued the yeast gpi18 deletion mutant,
      demonstrating conserved second-mannose-transfer function.
    action: ACCEPT
    reason: Cross-species genetic complementation directly supports the specific catalytic
      activity; core molecular function.
    supported_by:
    - reference_id: PMID:15623507
      supporting_text: Viability of the yeast gpi18 deletion mutant was restored by
        human PIG-V cDNA.
- term:
    id: GO:0000009
    label: alpha-1,6-mannosyltransferase activity
  evidence_type: IGI
  original_reference_id: PMID:15720390
  qualifier: enables
  review:
    summary: Genetic interaction evidence (IGI) with the yeast ortholog Ybr004c/GPI18
      (UniProtKB:P38211). Fabre et al. showed the human Ybr004cp homologue (PIGV)
      substitutes for the yeast protein in vivo, supporting alpha-1,6-mannosyltransferase
      activity in second-mannose addition. This is a correct parent of the specific
      GPI-MT-II activity.
    action: ACCEPT
    reason: Cross-species complementation supports the alpha-1,6-mannosyltransferase
      function; accurate parent term.
    supported_by:
    - reference_id: PMID:15720390
      supporting_text: The human Ybr004cp homologue can substitute for its S. cerevisiae
        counterpart in vivo.
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162873
  qualifier: located_in
  review:
    summary: Reactome (TAS) localization of the second-mannose-addition reaction (and
      PIGV) to the ER membrane, consistent with PIGV being a multi-pass ER membrane
      enzyme acting on the lumenal face.
    action: ACCEPT
    reason: Correct localization, curated from Reactome; consistent with experimental
      evidence.
    supported_by:
    - reference_id: Reactome:R-HSA-162873
      supporting_text: a second mannose residue is added to the glycolipid on the
        lumenal face of the endoplasmic reticulum membrane
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:15623507
  qualifier: located_in
  review:
    summary: Direct experimental evidence (IDA) that PIGV is an ER-membrane protein.
      Kang et al. characterized PIG-V as an ER-resident protein with multiple transmembrane
      regions and mapped its membrane topology, establishing ER membrane localization.
    action: ACCEPT
    reason: Experimentally determined localization; core cellular component. The multi-pass
      ER membrane topology is documented in UniProt.
    supported_by:
    - reference_id: PMID:15623507
      supporting_text: Human PIG-V encodes a 493-amino acid, endoplasmic reticulum
        (ER) resident protein with eight putative transmembrane regions.
    - reference_id: file:human/PIGV/PIGV-uniprot.txt
      supporting_text: Multi-pass membrane protein
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:15623507
  qualifier: involved_in
  review:
    summary: Direct experimental evidence (IMP) placing PIGV in GPI anchor biosynthesis,
      via characterization of PIG-V as the enzyme transferring the second mannose
      in GPI assembly. Core biological process.
    action: ACCEPT
    reason: Core biological process with direct experimental support.
    supported_by:
    - reference_id: PMID:15623507
      supporting_text: we suggest that PIG-V is the second mannosyltransferase in GPI
        anchor biosynthesis
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IGI
  original_reference_id: PMID:15623507
  qualifier: involved_in
  review:
    summary: Genetic interaction evidence (IGI) with yeast GPI18/YBR004C (UniProtKB:P38211)
      supporting the role of PIGV in GPI anchor biosynthesis, via cross-species complementation
      of the second-mannose-addition step.
    action: ACCEPT
    reason: Genetic complementation supports involvement in GPI anchor biosynthesis;
      core biological process.
    supported_by:
    - reference_id: PMID:15623507
      supporting_text: Viability of the yeast gpi18 deletion mutant was restored by
        human PIG-V cDNA.
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IGI
  original_reference_id: PMID:15720390
  qualifier: involved_in
  review:
    summary: Genetic interaction evidence (IGI) with yeast Ybr004c/GPI18 (UniProtKB:P38211).
      Fabre et al. showed Ybr004cp-depleted yeast accumulate a single-mannose GPI
      intermediate and cannot incorporate inositol into proteins, and that the human
      homologue (PIGV) complements the defect, supporting PIGV's role in GPI anchor
      biosynthesis.
    action: ACCEPT
    reason: Cross-species genetic evidence supports involvement in GPI anchor biosynthesis;
      core biological process.
    supported_by:
    - reference_id: PMID:15720390
      supporting_text: accumulate a GPI intermediate having a single mannose that
        is likely modified with ethanolamine phosphate
core_functions:
- description: Alpha-1,6-mannosyltransferase (GPI-MT-II) that transfers the second
    mannose from dolichyl-phosphate-mannose (Dol-P-Man) onto the Man1-GlcN-(acyl)PI
    GPI intermediate, forming the alpha-1,6 mannosyl linkage, during GPI-anchor biosynthesis
    on the lumenal face of the ER membrane.
  molecular_function:
    id: GO:0120563
    label: dol-P-Man:Man(1)GlcN-acyl-PI alpha-1,6-mannosyltransferase 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:15623507
    supporting_text: Here we report the cloning of PIG-V involved in transferring the
      second mannose in the GPI anchor.
  - reference_id: PMID:15720390
    supporting_text: A bioinformatics-based strategy identified the essential Saccharomyces
      cerevisiae Ybr004c protein as a candidate for the second GPI alpha-mannosyltransferase
      (GPI-MT-II).
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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:15623507
  title: PIG-V involved in transferring the second mannose in glycosylphosphatidylinositol.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Primary paper that cloned human PIG-V and identified it as GPI-MT-II,
      transferring the second mannose in GPI biosynthesis; defines catalytic activity,
      ER topology, and functional residues. Abstract-only in cache; full text underlies
      the experimental annotations.
- id: PMID:15720390
  title: Saccharomyces cerevisiae Ybr004c and its human homologue are required for
    addition of the second mannose during glycosylphosphatidylinositol precursor assembly.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Identifies yeast Ybr004c/GPI18 as GPI-MT-II and shows the human
      homologue (PIGV) complements it in vivo; supports the alpha-1,6-mannosyltransferase
      and GPI biosynthesis annotations.
- id: PMID:32814053
  title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
    and Uncovers Widespread Protein Aggregation in Affected Brains.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Large-scale yeast two-hybrid neurodegenerative-disease interactome;
      source of bare protein binding IPIs for PIGV that are uninformative about its
      molecular function.
- id: Reactome:R-HSA-162710
  title: Synthesis of glycosylphosphatidylinositol (GPI)
  findings: []
- id: Reactome:R-HSA-162873
  title: (ethanolamineP) mannose (a1-4) glucosaminyl-acyl-PI + dolichol phosphate
    D-mannose -> mannose (a1-6) (ethanolamineP) mannose (a1-4) glucosaminyl-acyl-PI
    + dolichol phosphate
  findings: []
- id: file:human/PIGV/PIGV-uniprot.txt
  title: UniProtKB Q9NUD9 (PIGV_HUMAN) entry
  findings: []