PIGN (GPI ethanolamine phosphate transferase 1; GPI-ET-I) is a multi-pass endoplasmic reticulum membrane protein that acts in glycosylphosphatidylinositol (GPI) anchor biosynthesis. It transfers ethanolamine phosphate from phosphatidylethanolamine onto the 2-OH of the first alpha-1,4-linked mannose of the GPI intermediate, one of three ethanolamine phosphate additions to the trimannosyl core (PIGN acts on mannose 1; the paralogs PIGO and PIGG act on mannoses 3 and 2). PIGN belongs to the PIGG/PIGN/PIGO family and localizes to the ER membrane, where the later steps of GPI assembly occur. Biallelic loss-of-function variants cause multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1), an autosomal recessive disorder of GPI-anchor biosynthesis characterized by neonatal hypotonia, seizures, dysmorphic features, and congenital anomalies.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | Summary: PIGN is a multi-pass ER membrane protein that carries out the ethanolamine phosphate transfer step of GPI-anchor biosynthesis in the ER; this phylogenetic (IBA) location annotation reflects the correct site of action and is a core localization. Reason: UniProt records the subcellular location as ER membrane (multi-pass membrane protein), consistent with the whole GPI-biosynthetic machinery residing in the ER, and the topology has 13 predicted transmembrane helices. This IBA is well supported and represents where PIGN functions. Supporting Evidence: file:human/PIGN/PIGN-uniprot.txt Endoplasmic reticulum membrane file:human/PIGN/PIGN-uniprot.txt Multi-pass membrane protein |
| GO:0006506 GPI anchor biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: PIGN participates in GPI-anchor biosynthesis, transferring ethanolamine phosphate onto the first mannose of the GPI intermediate. This phylogenetic annotation captures the core biological process. Reason: The UniProt PATHWAY line assigns PIGN to glycosylphosphatidylinositol-anchor biosynthesis, and its FUNCTION describes participation in a defined step of GPI biosynthesis. The IBA is consistent across orthologs (yeast MCD4, mouse Pign) and represents a core process. Supporting Evidence: file:human/PIGN/PIGN-uniprot.txt Glycolipid biosynthesis; glycosylphosphatidylinositol-anchor file:human/PIGN/PIGN-uniprot.txt participates in the eighth step of the |
| GO:0051377 mannose-ethanolamine phosphotransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: This is PIGN's core molecular function: transfer of ethanolamine phosphate from phosphatidylethanolamine onto a mannose of the GPI intermediate. The phylogenetic annotation is the correct, appropriately specific catalytic term. Reason: UniProt describes PIGN as an ethanolamine phosphate transferase that transfers EtNP from PE to the 2-OH of the first alpha-1,4-linked mannose of the GPI intermediate. GO:0051377 (mannose-ethanolamine phosphotransferase activity) is the exact catalytic term and is well conserved across the PIGN orthologs used for the IBA. Supporting Evidence: file:human/PIGN/PIGN-uniprot.txt Ethanolamine phosphate transferase that catalyzes an file:human/PIGN/PIGN-uniprot.txt ethanolamine phosphate (EtNP) transfer from phosphatidylethanolamine file:human/PIGN/PIGN-uniprot.txt the first alpha-1,4-linked mannose |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (InterPro/SubCell) annotation placing PIGN in the ER membrane; agrees with the curated UniProt location and the IBA. Reason: The InterPro signatures (IPR007070 GPI EtNP transferase 1, IPR017852) and UniProtKB-SubCell SL-0097 map to ER membrane, matching PIGN's curated location as a multi-pass ER membrane protein. Supporting Evidence: file:human/PIGN/PIGN-uniprot.txt Endoplasmic reticulum membrane |
| GO:0006506 GPI anchor biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation assigning PIGN to GPI-anchor biosynthesis via InterPro and UniPathway; consistent with the curated pathway and the IBA/TAS. Reason: InterPro GPI EtNP-transferase signatures and UniPathway UPA00196 (glycosylphosphatidylinositol-anchor biosynthesis) correctly place PIGN in this core process. Supporting Evidence: file:human/PIGN/PIGN-uniprot.txt Glycolipid biosynthesis; glycosylphosphatidylinositol-anchor |
| GO:0016020 membrane | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Generic InterPro-derived membrane localization. True but uninformative given the more specific ER membrane annotation that pinpoints where PIGN acts. Reason: PIGN is a multi-pass membrane protein, so a bare 'membrane' term is not wrong, but it is subsumed by the more specific and functionally correct GO:0005789 ER membrane annotation. The specific term should carry the localization. Supporting Evidence: file:human/PIGN/PIGN-uniprot.txt Multi-pass membrane protein |
| GO:0016740 transferase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Generic InterPro parent term for PIGN's transferase activity. Correct but far less informative than the specific mannose-ethanolamine phosphotransferase activity. Reason: GO:0016740 is a high-level ancestor of PIGN's actual catalytic term GO:0051377. It is not wrong, but the specific EtNP-transferase term should represent the molecular function; the parent adds no additional information. Supporting Evidence: file:human/PIGN/PIGN-uniprot.txt Ethanolamine phosphate transferase that catalyzes an |
| GO:0051377 mannose-ethanolamine phosphotransferase activity | IEA GO_REF:0000002 | ACCEPT | Summary: Electronic (InterPro) assignment of PIGN's specific catalytic activity, matching the IBA/ISS/TAS and the curated UniProt function. Reason: InterPro GPI EtNP-transferase 1 signatures (IPR007070, IPR037671) correctly predict the mannose-ethanolamine phosphotransferase activity that is PIGN's core molecular function. Supporting Evidence: file:human/PIGN/PIGN-uniprot.txt ethanolamine phosphate (EtNP) transfer from phosphatidylethanolamine |
| GO:0006506 GPI anchor biosynthetic process | TAS Reactome:R-HSA-162710 | ACCEPT | Summary: Reactome traceable-author annotation placing PIGN in the human GPI synthesis pathway. Consistent with the core biological process. Reason: Reactome pathway R-HSA-162710 (Synthesis of glycosylphosphatidylinositol) includes the EtNP-transfer reaction catalyzed by PIGN as one step of GPI-anchor biosynthesis; this is a well-established core process annotation. Supporting Evidence: Reactome:R-HSA-162710 GPI is synthesized in the endoplasmic reticulum |
| GO:0005829 cytosol | IDA GO_REF:0000052 | MARK AS OVER ANNOTATED | Summary: HPA immunofluorescence-based cytosolic localization. PIGN is a multi-pass ER membrane protein that functions on the lumenal/ER-membrane face during GPI assembly; a cytosolic pool is not its site of function. Reason: This is a high-throughput HPA IF annotation. PIGN's curated location is the ER membrane, and its 13-TM topology and role in GPI-anchor synthesis place its activity in the ER, not the bulk cytosol. A cytosolic signal most likely reflects antibody background or over-expression and is not the functional site. Retained (not removed) per policy, but flagged as over-annotated relative to the ER localization. Supporting Evidence: file:human/PIGN/PIGN-uniprot.txt Endoplasmic reticulum membrane |
| GO:0005886 plasma membrane | IDA GO_REF:0000052 | MARK AS OVER ANNOTATED | Summary: HPA immunofluorescence-based plasma membrane localization. PIGN acts in the ER membrane during GPI-anchor biosynthesis; the plasma membrane is where mature GPI-anchored proteins end up, not where PIGN itself functions. Reason: A plasma-membrane signal for an ER-resident biosynthetic enzyme is not its functional location. This HPA IF annotation likely reflects staining of the broader secretory/membrane compartment or antibody cross-reactivity; PIGN's curated and functional location is the ER membrane. Retained (not removed) per policy, but marked over-annotated. Supporting Evidence: file:human/PIGN/PIGN-uniprot.txt Endoplasmic reticulum membrane |
| GO:0005789 endoplasmic reticulum membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of the ER membrane location from the mouse ortholog (Q9R1S3). Matches the curated location and other evidence. Reason: ISS from mouse Pign (UniProtKB:Q9R1S3) correctly assigns the ER membrane location; this is PIGN's core site of action and is corroborated by IBA, IEA, and TAS evidence. Supporting Evidence: file:human/PIGN/PIGN-uniprot.txt Endoplasmic reticulum membrane |
| GO:0006506 GPI anchor biosynthetic process | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of the GPI-anchor biosynthetic process from mouse Pign. Consistent with PIGN's core role. Reason: ISS from mouse Pign (UniProtKB:Q9R1S3) assigns the GPI-anchor biosynthetic process, matching the curated pathway and PIGN's function as the EtNP transferase for the first mannose. Supporting Evidence: file:human/PIGN/PIGN-uniprot.txt participates in the eighth step of the |
| GO:0051377 mannose-ethanolamine phosphotransferase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity transfer of the EtNP-transferase activity from mouse Pign; this is PIGN's core molecular function and the UniProt EC/catalytic-activity block is itself inferred by similarity to the mouse enzyme. Reason: ISS from mouse Pign (UniProtKB:Q9R1S3) assigns mannose-ethanolamine phosphotransferase activity, matching PIGN's curated catalytic activity (EtNP transfer from PE to the first mannose of the GPI intermediate). Supporting Evidence: file:human/PIGN/PIGN-uniprot.txt Ethanolamine phosphate transferase that catalyzes an |
| GO:0051377 mannose-ethanolamine phosphotransferase activity | TAS Reactome:R-HSA-162798 | ACCEPT | Summary: Reactome traceable-author annotation of the specific EtNP-transfer reaction catalyzed by PIGN (phosphoethanolamine from PE onto the first mannose of the GPI precursor). Directly supports the core molecular function. Reason: Reactome reaction R-HSA-162798 describes the transfer of a phosphoethanolamine group from phosphatidylethanolamine onto the first mannose of the GPI precursor, the reaction PIGN catalyzes, mapping to GO:0051377. Supporting Evidence: Reactome:R-HSA-162798 a phosphoethanolamine group is transferred from phosphatidylethanolamine onto the first mannose of the GPI precursor |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | Summary: High-throughput mass-spectrometry detection of PIGN in an NK-cell membrane proteome. Confirms PIGN is a membrane protein but gives only a generic membrane location, not its functional ER-membrane site. Reason: The cited study is a bulk membrane-proteome MS survey of the YTS NK-like cell line that identified ~1843 proteins; detection in a crude membrane fraction supports only a generic 'membrane' term and is subsumed by the specific ER membrane annotation that reflects where PIGN acts. Supporting Evidence: PMID:19946888 Mass spectrometric analysis identified 1843 proteins with high confidence scores. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-162798 | ACCEPT | Summary: Reactome traceable-author annotation placing the PIGN-catalyzed EtNP-transfer reaction in the ER. Consistent with the core localization. Reason: Reactome annotates GPI synthesis, including the PIGN reaction R-HSA-162798, as occurring in the endoplasmic reticulum, matching PIGN's curated ER membrane location. Supporting Evidence: Reactome:R-HSA-162710 GPI is synthesized in the endoplasmic reticulum |
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