id: Q9H3S5
gene_symbol: PIGM
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: PIGM is the catalytic subunit of GPI mannosyltransferase I (GPI-MT-I),
  the enzyme that transfers the first mannose, in an alpha-1,4 linkage, from dolichyl-phosphate-mannose
  (Dol-P-Man) onto the glucosaminyl-(acyl)phosphatidylinositol (GlcN-(acyl)PI) intermediate
  during glycosylphosphatidylinositol (GPI) anchor biosynthesis. It is a multi-pass
  endoplasmic reticulum membrane protein whose catalytic DXD motif faces the ER lumen,
  so this mannosylation step occurs on the lumenal side of the ER membrane. PIGM acts
  together with the stabilizing subunit PIGX to form the GPI-MT-I complex. Loss of
  PIGM function causes an inherited GPI deficiency (GPI biosynthesis defect); a hypomorphic
  PIGM promoter mutation is associated with portal and cerebral vein thrombosis and
  atypical absence seizures.
existing_annotations:
- term:
    id: GO:0000030
    label: mannosyltransferase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: General mannosyltransferase activity, assigned by phylogenetic inference.
      This is correct but far less specific than PIGM's characterized activity (transfer
      of the first GPI mannose via an alpha-1,4 bond from Dol-P-Man), which is captured
      by GO:0180041.
    action: MODIFY
    reason: The annotation is in the right molecular-function branch but is too general.
      PIGM is a specific GPI alpha-1,4-mannosyltransferase (GPI-MT-I); the specific
      term GO:0180041 (also present in GOA with IDA support) should be preferred.
    proposed_replacement_terms:
    - id: GO:0180041
      label: dol-P-Man:GlcN-acyl-PI alpha-1,4-mannosyltransferase activity
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - GRANULARITY_MISMATCH
    supported_by:
    - reference_id: PMID:32156170
      supporting_text: PIGM and PIGV are GPI-mannosyltransferase (MT) I and II, respectively
- term:
    id: GO:1990529
    label: glycosylphosphatidylinositol-mannosyltransferase I complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: PIGM is part of the GPI-mannosyltransferase I complex, which in mammals
      comprises the catalytic subunit PIGM and the stabilizing subunit PIGX. This
      is the correct complex assignment for PIGM.
    action: ACCEPT
    reason: The GPI-MT-I complex membership is well established; PIGM is its catalytic
      subunit and PIGX stabilizes it.
    supported_by:
    - reference_id: PMID:32156170
      supporting_text: PIGM functions in association with PIGX, which stabilizes PIGM
    - reference_id: file:human/PIGM/PIGM-uniprot.txt
      supporting_text: complex that is composed of PIGM and PIGX
- term:
    id: GO:0006506
    label: GPI anchor biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: PIGM catalyzes step 6 of GPI-anchor biosynthesis (addition of the first
      mannose), so involvement in the GPI anchor biosynthetic process is the core
      biological process for this gene.
    action: ACCEPT
    reason: Well-supported core biological process; consistent with the experimental
      IDA annotation to the same term.
    supported_by:
    - reference_id: PMID:11226175
      supporting_text: PIG-M transfers the first mannose to glycosylphosphatidylinositol
        on the lumenal
- term:
    id: GO:0004376
    label: GPI mannosyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based (IPR007704, PIG-M) electronic annotation to GPI mannosyltransferase
      activity. This is accurate for PIGM but less specific than the characterized
      dol-P-Man:GlcN-acyl-PI alpha-1,4-mannosyltransferase activity (GO:0180041).
    action: MODIFY
    reason: Correct branch and biologically accurate, but the specific characterized
      activity term (GO:0180041) is preferable as the representative molecular function.
    proposed_replacement_terms:
    - id: GO:0180041
      label: dol-P-Man:GlcN-acyl-PI alpha-1,4-mannosyltransferase activity
    supported_by:
    - reference_id: PMID:11226175
      supporting_text: PIG-M transfers the first mannose to glycosylphosphatidylinositol
        on the lumenal
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic annotation from UniProt Subcellular Location mapping to ER
      membrane, consistent with the experimental IDA localization (PMID:11226175)
      and the multi-pass ER membrane topology.
    action: ACCEPT
    reason: Correct localization, corroborated by experimental evidence.
    supported_by:
    - reference_id: file:human/PIGM/PIGM-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: Electronic annotation (InterPro/UniPathway) to GPI anchor biosynthetic
      process, redundant with and consistent with the IBA and IDA annotations to the
      same term.
    action: ACCEPT
    reason: Correct core biological process; supported by experimental evidence.
    supported_by:
    - reference_id: PMID:11226175
      supporting_text: PIG-M transfers the first mannose to glycosylphosphatidylinositol
        on the lumenal
- term:
    id: GO:0016020
    label: membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: located_in
  review:
    summary: Generic membrane localization from InterPro. PIGM is a multi-pass ER
      membrane protein, so this is correct but uninformatively broad relative to the
      ER membrane annotation (GO:0005789).
    action: MARK_AS_OVER_ANNOTATED
    reason: Not wrong, but subsumed by the more specific and experimentally supported
      GO:0005789 (endoplasmic reticulum membrane); the bare 'membrane' term adds little.
    supported_by:
    - reference_id: file:human/PIGM/PIGM-uniprot.txt
      supporting_text: Multi-pass membrane protein
- term:
    id: GO:0051751
    label: alpha-1,4-mannosyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based annotation to alpha-1,4-mannosyltransferase activity.
      PIGM does form an alpha-1,4 mannosidic bond, so this is accurate, but it is
      more general than the specific GPI substrate reaction (GO:0180041).
    action: MODIFY
    reason: Correct linkage-level activity but less specific than the characterized
      dol-P-Man:GlcN-acyl-PI alpha-1,4-mannosyltransferase activity; GO:0180041 is
      preferred.
    proposed_replacement_terms:
    - id: GO:0180041
      label: dol-P-Man:GlcN-acyl-PI alpha-1,4-mannosyltransferase activity
    supported_by:
    - reference_id: file:human/PIGM/PIGM-uniprot.txt
      supporting_text: transfer of the first mannose, via an alpha-1,4 bond from a
        dolichol-phosphate-mannose
- term:
    id: GO:0180041
    label: dol-P-Man:GlcN-acyl-PI alpha-1,4-mannosyltransferase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: Rhea-based electronic annotation (RHEA:60500) to the specific catalytic
      activity of PIGM. This exactly matches the UniProt catalytic activity and the
      experimental IDA annotation to the same term, and is the representative molecular
      function of PIGM.
    action: ACCEPT
    reason: This is the precise, correct molecular function of PIGM and is independently
      supported by experimental evidence (PMID:11226175) and the UniProt Rhea reaction.
    supported_by:
    - reference_id: PMID:11226175
      supporting_text: PIG-M transfers the first mannose to glycosylphosphatidylinositol
        on the lumenal
    - reference_id: file:human/PIGM/PIGM-uniprot.txt
      supporting_text: transfer of the first mannose, via an alpha-1,4 bond from a
        dolichol-phosphate-mannose
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: High-throughput AP-MS interaction (BioPlex 2.0) recording binding to
      STARD7 (UniProtKB:Q9NQZ5). 'Protein binding' is uninformative and the partner
      captured here is not the functional GPI-MT-I subunit (PIGX); STARD7 is a phosphatidylcholine
      transfer protein, so this is most likely an incidental proteome-scale co-purification.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare 'protein binding' from a genome-scale interactome screen does not
      convey a specific molecular function and the STARD7 interaction is not the biologically
      characterized GPI-MT-I partnership; retained but flagged rather than removed,
      per policy on experimental IPIs.
    supported_by:
    - reference_id: file:human/PIGM/PIGM-uniprot.txt
      supporting_text: 'Q9NQZ5: STARD7; NbExp=2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: High-throughput AP-MS interaction (BioPlex 3.0) again recording binding
      to STARD7 (UniProtKB:Q9NQZ5). As with the BioPlex 2.0 annotation, 'protein binding'
      is uninformative and STARD7 is not the functional GPI-MT-I partner.
    action: MARK_AS_OVER_ANNOTATED
    reason: Duplicate uninformative bare 'protein binding' from a proteome-scale interactome;
      does not represent a specific molecular function. Retained but flagged rather
      than removed, per policy on experimental IPIs.
    supported_by:
    - reference_id: file:human/PIGM/PIGM-uniprot.txt
      supporting_text: 'Q9NQZ5: STARD7; NbExp=2'
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: NAS
  original_reference_id: PMID:32156170
  qualifier: located_in
  review:
    summary: ComplexPortal (CPX-2697) assertion that PIGM localizes to the ER membrane,
      where GPI biosynthesis takes place. Consistent with experimental and electronic
      ER-membrane annotations.
    action: ACCEPT
    reason: Correct localization; GPI is assembled on the ER membrane and PIGM is
      a multi-pass ER membrane protein.
    supported_by:
    - reference_id: PMID:32156170
      supporting_text: PIGM and PIGV are GPI-mannosyltransferase (MT) I and II, respectively
    - reference_id: file:human/PIGM/PIGM-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Endoplasmic reticulum membrane'
- term:
    id: GO:1990529
    label: glycosylphosphatidylinositol-mannosyltransferase I complex
  evidence_type: NAS
  original_reference_id: PMID:32156170
  qualifier: part_of
  review:
    summary: ComplexPortal (CPX-2697) assertion of PIGM membership in the GPI-mannosyltransferase
      I complex (PIGM + PIGX). Correct and consistent with the IBA and ISS annotations
      to the same complex.
    action: ACCEPT
    reason: Well-supported complex membership; PIGM is the catalytic subunit of GPI-MT-I.
    supported_by:
    - reference_id: PMID:32156170
      supporting_text: PIGM functions in association with PIGX, which stabilizes PIGM
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:11226175
  qualifier: located_in
  review:
    summary: Direct experimental localization of PIG-M to the ER membrane; the catalytic
      DXD motif faces the ER lumen, showing that PIGM is an ER membrane protein acting
      on the lumenal side.
    action: ACCEPT
    reason: Experimental (IDA) ER membrane localization, corroborated by the multi-pass
      ER membrane topology; this is the core localization.
    supported_by:
    - reference_id: PMID:11226175
      supporting_text: PIG-M has a functionally important DXD motif, a characteristic
        of many
    - reference_id: file:human/PIGM/PIGM-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:11226175
  qualifier: involved_in
  review:
    summary: Direct experimental demonstration that PIG-M is required for and catalyzes
      the addition of the first mannose in GPI biosynthesis (identified via a GPI-MT-I-defective
      human cell line rescued by PIG-M). This is the core biological process of PIGM.
    action: ACCEPT
    reason: Strong experimental (IDA) support for the core GPI-anchor biosynthetic
      role.
    supported_by:
    - reference_id: PMID:11226175
      supporting_text: PIG-M transfers the first mannose to glycosylphosphatidylinositol
        on the lumenal
- term:
    id: GO:0180041
    label: dol-P-Man:GlcN-acyl-PI alpha-1,4-mannosyltransferase activity
  evidence_type: IDA
  original_reference_id: PMID:11226175
  qualifier: enables
  review:
    summary: Direct experimental evidence for the specific catalytic activity of PIG-M,
      transfer of the first mannose via an alpha-1,4 bond from Dol-P-Man to GlcN-(acyl)PI,
      on the lumenal side of the ER; mutation of the DXD motif (D49/D51) abolishes
      activity. This is the representative molecular function of PIGM.
    action: ACCEPT
    reason: Precise, experimentally established (IDA) molecular function; the DXD-motif
      mutagenesis confirms catalytic requirement.
    supported_by:
    - reference_id: PMID:11226175
      supporting_text: PIG-M has a functionally important DXD motif, a characteristic
        of many
    - reference_id: file:human/PIGM/PIGM-uniprot.txt
      supporting_text: transfer of the first mannose, via an alpha-1,4 bond from a
        dolichol-phosphate-mannose
- term:
    id: GO:1990529
    label: glycosylphosphatidylinositol-mannosyltransferase I complex
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: part_of
  review:
    summary: Sequence-similarity transfer (from mouse Pigm, UniProtKB:Q9EQY6) of membership
      in the GPI-MT-I complex. Consistent with the IBA and NAS annotations to the
      same complex.
    action: ACCEPT
    reason: Correct complex membership, corroborated by orthology and by ComplexPortal.
    supported_by:
    - reference_id: file:human/PIGM/PIGM-uniprot.txt
      supporting_text: complex that is composed of PIGM and PIGX
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-162830
  qualifier: located_in
  review:
    summary: Reactome traceable assertion placing the PIG-M/PIG-X-catalyzed first-mannose
      addition (step 6 of GPI synthesis) at the lumenal surface of the ER membrane.
      Consistent with the experimental ER-membrane localization.
    action: ACCEPT
    reason: Correct localization from an authoritative pathway resource; matches experimental
      evidence.
    supported_by:
    - reference_id: Reactome:R-HSA-162830
      supporting_text: In the fifth step of GPI synthesis, a mannose residue is added
        to glucosaminyl-acyl-PI
core_functions:
- description: PIGM is the catalytic subunit of GPI mannosyltransferase I; it transfers
    the first mannose in an alpha-1,4 linkage from dolichyl-phosphate-mannose (Dol-P-Man)
    onto the GlcN-(acyl)PI intermediate during GPI-anchor biosynthesis, acting on
    the lumenal side of the ER membrane.
  molecular_function:
    id: GO:0180041
    label: dol-P-Man:GlcN-acyl-PI alpha-1,4-mannosyltransferase activity
  directly_involved_in:
  - id: GO:0006506
    label: GPI anchor biosynthetic process
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  in_complex:
    id: GO:1990529
    label: glycosylphosphatidylinositol-mannosyltransferase I complex
  supported_by:
  - reference_id: PMID:11226175
    supporting_text: PIG-M transfers the first mannose to glycosylphosphatidylinositol
      on the lumenal
  - reference_id: file:human/PIGM/PIGM-uniprot.txt
    supporting_text: transfer of the first mannose, via an alpha-1,4 bond from a dolichol-phosphate-mannose
proposed_new_terms: []
suggested_questions:
- question: Does the STARD7 interaction captured in BioPlex have any physiological
    relevance to GPI-MT-I function or ER lipid supply, or is it an incidental proteome-scale
    co-purification?
suggested_experiments:
- description: Structural determination of the human PIGM-PIGX GPI-MT-I complex to
    define the Dol-P-Man and GlcN-(acyl)PI binding sites and the role of the lumenal
    DXD motif.
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:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:11226175
  title: PIG-M transfers the first mannose to glycosylphosphatidylinositol on the
    lumenal side of the ER.
  findings:
  - statement: PIG-M is the catalytic mannosyltransferase that adds the first mannose
      to GPI via an alpha-1,4 bond on the lumenal side of the ER, using a lumen-facing
      DXD motif essential for activity.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; the defining functional and localization paper
      for PIGM/GPI-MT-I. Cached entry is abstract-only, but the abstract plus UniProt
      (which cites this PMID for FUNCTION, catalytic activity and mutagenesis) support
      the annotations.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioPlex 2.0 proteome-scale AP-MS; source of an uninformative 'protein
      binding' (STARD7) IPI. Correctly cited but low relevance to PIGM's characterized
      function.
- id: PMID:32156170
  title: Biosynthesis and biology of mammalian GPI-anchored proteins.
  findings:
  - statement: PIGM and PIGV are GPI-mannosyltransferases I and II; PIGM adds Man1
      and functions in association with PIGX, which stabilizes PIGM.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Authoritative Kinoshita review; full text available and directly
      supports PIGM's role as GPI-MTI and its PIGX partnership.
- id: PMID:33961781
  title: Dual proteome-scale networks reveal cell-specific remodeling of the human
    interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: BioPlex 3.0 proteome-scale AP-MS; source of a duplicate uninformative
      'protein binding' (STARD7) IPI. Correctly cited but low relevance.
- id: Reactome:R-HSA-162830
  title: glucosaminyl-acyl-PI + dolichol phosphate D-mannose -> mannose(al1-4)glucosaminyl-acyl-PI
    + dolichol phosphate
  findings:
  - statement: Reactome reaction for the PIG-M/PIG-X-catalyzed addition of the first
      mannose to glucosaminyl-acyl-PI at the lumenal surface of the ER membrane.
    reference_section_type: RESULTS
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Reactome reaction cited by GOA for ER-membrane localization; describes
      the exact PIGM-catalyzed step.
- id: file:human/PIGM/PIGM-uniprot.txt
  title: UniProtKB Q9H3S5 PIGM record
  findings:
  - statement: UniProt describes PIGM as the catalytic subunit of the GPI-mannosyltransferase
      I complex (with PIGX), a multi-pass ER membrane protein that transfers the first
      mannose via an alpha-1,4 bond from Dol-P-Man to GlcN-(acyl)PI.
    reference_section_type: OTHER
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: UniProt record for Q9H3S5; used for catalytic activity, subunit
      composition, and subcellular location statements.