Affinage

PIGQ

Phosphatidylinositol N-acetylglucosaminyltransferase subunit Q · UniProt Q9BRB3

Length
760 aa
Mass
84.1 kDa
Annotated
2026-06-10
14 papers in source corpus 7 papers cited in narrative 7 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PIGQ (hGPI1) is a subunit of the GPI-N-acetylglucosaminyltransferase (GPI-GnT) complex in the endoplasmic reticulum membrane, where it acts with PIG-A, PIG-H, and PIG-C to catalyze the first committed step of glycosylphosphatidylinositol (GPI) anchor biosynthesis — transfer of GlcNAc from UDP-GlcNAc to phosphatidylinositol (PMID:9463366). The reconstituted four-component complex carries out GlcNAc transfer but not the subsequent de-N-acetylation step, and recognizes the fatty acyl chains of phosphatidylinositol substrate (PMID:9463366). Rather than contributing catalytic activity, PIGQ serves a scaffolding/stabilization role: it ties PIG-C into the PIG-A/PIG-H sub-complex, and its loss causes near-complete destabilization of the trimeric PIG-A/PIG-H/PIG-C complex while the PIG-A/PIG-H binary complex persists (PMID:10373468). Loss of PIGQ function reduces surface expression of GPI-anchored proteins in human cells (PMID:11418246, PMID:32588908), and the gene's role is conserved across kingdoms, with yeast and Plasmodium orthologs supporting GPI assembly (PMID:8910381, PMID:11849707). Biallelic pathogenic PIGQ variants cause an inherited GPI-deficiency disorder, established by reduced GPI-anchored protein expression on patient cells and rescue with wild-type PIGQ cDNA (PMID:32588908).

Mechanistic history

Synthesis pass · year-by-year structured walk · 7 steps
  1. 1996 High

    Establishing whether GPI1 is genetically required for the first step of GPI anchor assembly, which was needed to place the gene in the biosynthetic pathway.

    Evidence Gene disruption in S. cerevisiae with in vitro enzymatic assay and radiolabeled inositol incorporation

    PMID:8910381

    Open questions at the time
    • Did not define whether Gpi1p is catalytic or structural
    • Worked in yeast ortholog, not human protein
    • Did not identify the partner subunits of the complex
  2. 1998 High

    Defining the physical composition and enzymatic output of the human GPI-GnT complex, which assigned PIGQ to a specific multi-subunit enzyme.

    Evidence Co-immunoprecipitation, in vitro GPI-GnT enzymatic assay, and ER fractionation

    PMID:9463366

    Open questions at the time
    • Did not resolve which subunit carries catalysis
    • Did not establish stoichiometry or assembly order
    • No structural model of the complex
  3. 1999 High

    Resolving PIGQ's role within the complex — scaffolding versus catalysis — by testing how its loss affects complex integrity.

    Evidence Homologous-recombination knockout of GPI1 in mouse F9 cells with reciprocal Co-IP and subunit Western quantification

    PMID:10373468

    Open questions at the time
    • Did not map the PIGQ surface that contacts PIG-C
    • Mechanism by which loss reduces PIG-C/PIG-H protein levels not defined
    • No structural basis for stabilization
  4. 2001 Medium

    Confirming PIGQ is required for GPI biosynthesis in human cells and mapping the locus, extending the model beyond yeast and mouse.

    Evidence Antisense RNA knockdown with GPI-reporter flow cytometry and chromosomal mapping in HEK293 cells

    PMID:11418246

    Open questions at the time
    • Knockdown was incomplete, so null phenotype not fully resolved
    • Heterozygous deletion produced no overt phenotype, leaving dosage sensitivity unclear
    • Single lab
  5. 2002 Medium

    Testing cross-kingdom conservation of PIGQ function by heterologous complementation.

    Evidence Complementation of yeast gpi1 mutant by P. falciparum GPI1

    PMID:11849707

    Open questions at the time
    • Provides conservation evidence but no mechanistic detail for the human protein
    • Single study
  6. 2020 Medium

    Demonstrating that human PIGQ variants are directly causal for impaired GPI anchoring, linking the gene to inherited disease.

    Evidence Flow cytometry of GPI-anchored proteins on patient cells with wild-type PIGQ cDNA rescue

    PMID:32588908

    Open questions at the time
    • Single study
    • Genotype-phenotype correlation across variants not established
    • Residual GPI synthesis in patient cells not quantified mechanistically
  7. 2025 Low

    Extending the catalogue of pathogenic PIGQ alleles by validating a novel missense variant.

    Evidence Functional complementation assay in CHO cells

    PMID:40718141

    Open questions at the time
    • Single functional assay, single study, minimal mechanistic detail
    • Effect on complex stability not assessed
    • No structural interpretation of the missense substitution

Open questions

Synthesis pass · forward-looking unresolved questions
  • A structural model of how PIGQ bridges PIG-C into the PIG-A/PIG-H complex, and the molecular basis by which individual missense variants destabilize the GPI-GnT complex, remains undefined.
  • No atomic structure of the GPI-GnT complex or PIGQ contact surfaces
  • Variant-specific effects on complex assembly uncharacterized
  • Substrate acyl-chain recognition mechanism not mapped to a subunit

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 2 GO:0060089 molecular transducer activity 1
Localization
GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-392499 Metabolism of proteins 2
Partners
PIGAPIGCPIGH
Complex memberships
GPI-GlcNAc transferase (GPI-GnT) complex

Evidence

Reading pass · 7 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 PIGQ (hGPI1) forms a protein complex in the endoplasmic reticulum membrane with PIG-A, PIG-H, and PIG-C; this four-component complex mediates GPI-GlcNAc transferase (GPI-GnT) activity in vitro, catalyzing the first step of GPI biosynthesis (transfer of N-acetylglucosamine from UDP-GlcNAc to phosphatidylinositol). The complex did not mediate the second reaction (GlcNAc-PI de-N-acetylation), and the complex showed ~100-fold preference for bovine PI over soybean PI, suggesting the enzyme recognizes the fatty acyl chains of PI. Co-immunoprecipitation, in vitro GPI-GnT enzymatic assay, subcellular fractionation (ER membrane localization) The EMBO journal High 9463366
1996 Yeast GPI1 (ortholog of human PIGQ) is required for N-acetylglucosaminylphosphatidylinositol synthesis (first step of GPI anchor assembly). Disruption of GPI1 in S. cerevisiae abolished in vitro N-acetylglucosaminylphosphatidylinositol synthetic activity and blocked inositol incorporation into protein. Loss of Gpi1p caused a cell separation defect and defective ascospore wall maturation, demonstrating a role in morphogenesis. Gene disruption/knockout, in vitro enzymatic assay, radiolabeled inositol incorporation, complementation cloning The Journal of biological chemistry High 8910381
1999 GPI1 stabilizes the GPI-GnT complex by tying PIG-C into the PIG-A/PIG-H/PIG-C/GPI1 complex. Disruption of mouse GPI1 in F9 cells caused near-complete loss of the PIG-A/PIG-H/PIG-C trimeric complex (though the PIG-A/PIG-H binary complex was still detectable) and partial decreases in PIG-C and PIG-H protein levels, indicating a scaffolding/stabilization role for GPI1 rather than direct catalysis. Gene disruption by homologous recombination in mouse F9 cells, co-immunoprecipitation of complex components, Western blot quantification of subunit levels The Journal of biological chemistry High 10373468
2001 Human GPI1 (PIGQ) is required for efficient GPI biosynthesis in human cells. Antisense RNA-mediated knockdown of GPI1 in HEK293 cells caused a marked but incomplete decrease in expression of a GPI-linked reporter protein, confirming GPI1's role in GPI anchor biosynthesis. The GPI1 locus was mapped to chromosome 16p13.3. Heterozygous deletion of one GPI1 allele (in alpha-thalassaemia/mental retardation syndrome patients) does not produce an overt defect in GPI-linked protein expression. Antisense RNA knockdown, GPI-reporter protein expression assay (flow cytometry), chromosomal mapping, analysis of patient cell lines Gene Medium 11418246
2002 The Plasmodium falciparum GPI1 homolog (PfGPI1) functionally complements a S. cerevisiae gpi1 mutant, rescuing GPI anchor synthesis defects, establishing conservation of the GPI1 scaffolding/complex function across kingdoms. Heterologous complementation of yeast gpi1 mutant by P. falciparum GPI1 Molecular and biochemical parasitology Medium 11849707
2020 Biallelic pathogenic variants in human PIGQ cause reduced expression of GPI-anchored proteins on granulocytes and fibroblasts (demonstrated by flow cytometry). Transfection of wild-type PIGQ cDNA into patient fibroblasts rescued GPI-anchored protein expression, providing the first functional evidence in human cells that PIGQ variants directly impair GPI anchoring. Flow cytometry of GPI-anchored proteins on patient-derived cells, rescue by wild-type PIGQ cDNA transfection Journal of inherited metabolic disease Medium 32588908
2025 A novel PIGQ missense variant (c.1370T>G, p.Leu457Arg) was validated as pathogenic by functional study in Chinese hamster ovarian cells, confirming that this variant impairs GPI biosynthesis. Functional complementation assay in CHO cells Frontiers in genetics Low 40718141

Source papers

Stage 0 corpus · 14 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 The first step of glycosylphosphatidylinositol biosynthesis is mediated by a complex of PIG-A, PIG-H, PIG-C and GPI1. The EMBO journal 129 9463366
1996 Gpi1, a Saccharomyces cerevisiae protein that participates in the first step in glycosylphosphatidylinositol anchor synthesis. The Journal of biological chemistry 73 8910381
1999 GPI1 stabilizes an enzyme essential in the first step of glycosylphosphatidylinositol biosynthesis. The Journal of biological chemistry 31 10373468
1985 Onset of paternal and maternal Gpi-1 expression in preimplantation mouse embryos. Developmental biology 25 3996761
2020 Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ: Report of seven new subjects and review of the literature. Journal of inherited metabolic disease 23 32588908
2002 The GPI1 homologue from Plasmodium falciparum complements a Saccharomyces cerevisiae GPI1 anchoring mutant. Molecular and biochemical parasitology 17 11849707
1981 Genetic variation for prolidase (PEP-4) in the mouse maps near the gene for glucosephosphate isomerase (GPI-1) on chromosome 7. Biochemical genetics 14 7295293
2019 PIGQ glycosylphosphatidylinositol-anchored protein deficiency: Characterizing the phenotype. American journal of medical genetics. Part A 12 31148362
2001 The human GPI1 gene is required for efficient glycosylphosphatidylinositol biosynthesis. Gene 11 11418246
1985 Glucosephosphate isomerase (GPI-1) expression in mouse ova: cis regulation of monomer realization. Biochemical genetics 11 4084208
2021 PIGQ-Related Glycophosphatidylinositol Deficiency Associated with Nonprogressive Congenital Ataxia. Cerebellum (London, England) 6 34089469
2024 Perturbation of the insomnia WDR90 genome-wide association studies locus pinpoints rs3752495 as a causal variant influencing distal expression of neighboring gene, PIG-Q. Sleep 3 38571402
2023 Perturbation of the insomnia WDR90 GWAS locus pinpoints rs3752495 as a causal variant influencing distal expression of neighboring gene, PIG-Q. bioRxiv : the preprint server for biology 1 37645863
2025 Two novel cases with PIGQ-CDG: expansion of the genotype-phenotype spectrum and evaluation of GestaltMatcher as a diagnostic tool. Frontiers in genetics 0 40718141

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