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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | 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. Reason: The phylogenetically inferred ER membrane localization matches the experimental and homology-based evidence and the known site of GPI biosynthesis. Supporting Evidence: PMID:32156170 The core GPI is assembled on the endoplasmic reticulum (ER) membrane file:human/PIGO/PIGO-uniprot.txt Endoplasmic reticulum membrane |
| GO:0006506 GPI anchor biosynthetic process | IBA GO_REF:0000033 | ACCEPT | 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. Reason: Directly supported by the biosynthetic role established in the literature and UniProt pathway annotation. Supporting Evidence: PMID:32156170 Two EtNPs are sequentially transferred to the 6-positions of Man3 and then Man2 by PIGO file:human/PIGO/PIGO-uniprot.txt participates in the tenth step of the glycosylphosphatidylinositol- |
| GO:0051377 mannose-ethanolamine phosphotransferase activity | IBA GO_REF:0000033 | ACCEPT | 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. 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. Supporting Evidence: PMID:32156170 Two EtNPs are sequentially transferred to the 6-positions of Man3 and then Man2 by PIGO file:human/PIGO/PIGO-uniprot.txt transfers an ethanolamine phosphate (EtNP) from a |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt SubCellular Location mapping to ER membrane; consistent with the multi-pass ER membrane topology and the ER site of GPI assembly. Reason: Correct localization; concordant with the IBA, ISS and NAS ER membrane annotations. Supporting Evidence: file:human/PIGO/PIGO-uniprot.txt Endoplasmic reticulum membrane |
| GO:0006506 GPI anchor biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (ARBA/InterPro/UniPathway) assignment to GPI-anchor biosynthesis, matching PIGO's role in the core GPI assembly pathway. Reason: Correct core process; agrees with experimental (IMP) and phylogenetic (IBA) annotations to the same term. Supporting Evidence: file:human/PIGO/PIGO-uniprot.txt participates in the tenth step of the glycosylphosphatidylinositol- |
| GO:0016772 transferase activity, transferring phosphorus-containing groups | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: file:human/PIGO/PIGO-uniprot.txt transfers an ethanolamine phosphate (EtNP) from a |
| GO:0051377 mannose-ethanolamine phosphotransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Automated (ARBA/InterPro) assignment of the correct specific molecular function of PIGO. Reason: Matches PIGO's characterized catalytic activity and the IBA/IMP annotations to the same term. Supporting Evidence: file:human/PIGO/PIGO-uniprot.txt transfers an ethanolamine phosphate (EtNP) from a |
| GO:0005789 endoplasmic reticulum membrane | ISS GO_REF:0000024 | ACCEPT | Summary: ER membrane localization transferred by sequence similarity from the mouse ortholog (UniProtKB:Q9JJI6). Consistent with all other localization evidence. Reason: Correct localization supported by ortholog data and the ER site of GPI biosynthesis. Supporting Evidence: file:human/PIGO/PIGO-uniprot.txt Endoplasmic reticulum membrane |
| GO:0006506 GPI anchor biosynthetic process | IMP PMID:24417746 PIGO mutations in intractable epilepsy and severe developmen... | ACCEPT | 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. 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. Supporting Evidence: PMID:24417746 Our findings therefore expand the clinical spectrum of file:human/PIGO/PIGO-uniprot.txt decrease in mannose-ethanolamine |
| GO:0006506 GPI anchor biosynthetic process | IMP PMID:28337824 Phenotype-genotype correlations of PIGO deficiency with vari... | ACCEPT | 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. Reason: Functional analyses in a PIGO-deficient cell line link PIGO loss to defective GPI biosynthesis; concordant with UniProt catalytic/variant annotation. Supporting Evidence: PMID:28337824 PIGO deficiency shows characteristic features, such as Hirschsprung disease, file:human/PIGO/PIGO-uniprot.txt decrease in mannose-ethanolamine |
| GO:0051377 mannose-ethanolamine phosphotransferase activity | IMP PMID:24417746 PIGO mutations in intractable epilepsy and severe developmen... | ACCEPT | Summary: The PIGO T130N patient variant decreases mannose-ethanolamine phosphotransferase activity, providing experimental (mutation) support that PIGO enables this molecular function. 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. Supporting Evidence: file:human/PIGO/PIGO-uniprot.txt decrease in mannose-ethanolamine PMID:24417746 Our findings therefore expand the clinical spectrum of |
| GO:0051377 mannose-ethanolamine phosphotransferase activity | IMP PMID:28337824 Phenotype-genotype correlations of PIGO deficiency with vari... | ACCEPT | 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. Reason: Directed mutagenesis / patient-variant activity assays demonstrate PIGO enables the specific EtNP-transferase activity; concordant with UniProt. Supporting Evidence: file:human/PIGO/PIGO-uniprot.txt decrease in mannose-ethanolamine PMID:28337824 functional analysis |
| GO:0006506 GPI anchor biosynthetic process | IMP PMID:24049131 Vitamin B6-responsive epilepsy due to inherited GPI deficien... | ACCEPT | Summary: Inherited GPI deficiency due to PIGO mutation (R119W), presenting as vitamin B6-responsive epilepsy; loss of PIGO function impairs GPI-anchor biosynthesis. 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. Supporting Evidence: PMID:24049131 Vitamin B6-responsive epilepsy due to inherited GPI deficiency file:human/PIGO/PIGO-uniprot.txt decrease in mannose-ethanolamine |
| GO:0005789 endoplasmic reticulum membrane | NAS PMID:32156170 Biosynthesis and biology of mammalian GPI-anchored proteins. | ACCEPT | 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. Reason: Author statement consistent with all other ER membrane evidence and the known site of GPI assembly. Supporting Evidence: PMID:32156170 The core GPI is assembled on the endoplasmic reticulum (ER) membrane |
| GO:0051377 mannose-ethanolamine phosphotransferase activity | IMP PMID:24049131 Vitamin B6-responsive epilepsy due to inherited GPI deficien... | ACCEPT | Summary: The PIGO R119W patient variant decreases mannose-ethanolamine phosphotransferase activity, supporting that PIGO enables this molecular function. Reason: Variant functional evidence for PIGO's specific catalytic activity; concordant with UniProt catalytic-activity annotation (ECO:0000305 from this paper). Supporting Evidence: file:human/PIGO/PIGO-uniprot.txt decrease in mannose-ethanolamine PMID:24049131 Vitamin B6-responsive epilepsy due to inherited GPI deficiency |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: PMID:19946888 approximately 40% of the identified proteins were predicted as plausible membrane proteins |
| GO:0006506 GPI anchor biosynthetic process | ISS GO_REF:0000024 | ACCEPT | Summary: GPI-anchor biosynthesis role transferred by sequence similarity from the mouse ortholog (UniProtKB:Q9JJI6). Core process for PIGO. Reason: Correct core biological process; concordant with experimental (IMP), automated (IEA) and phylogenetic (IBA) annotations to the same term. Supporting Evidence: file:human/PIGO/PIGO-uniprot.txt participates in the tenth step of the glycosylphosphatidylinositol- |
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