PIGC

PIGC (the human homologue of yeast GPI2) is an endoplasmic reticulum membrane protein that acts as an essential subunit of the GPI-GlcNAc transferase (GPI-GnT) complex, which catalyzes the first committed step of glycosylphosphatidylinositol anchor biosynthesis—transfer of N-acetylglucosamine from UDP-GlcNAc to phosphatidylinositol (PMID:9463366, PMID:8806613). Within this ER-resident complex PIGC associates physically with PIG-A, PIG-H, and hGPI1, and the assembled complex exhibits GlcNAc transferase activity in vitro with strong preference for substrate PI bearing particular fatty acyl chains (PMID:9463366). The functional partnership between PIGC and the hGPI1 subunit is conserved from yeast, where overexpression of GPI2 suppresses a gpi1 temperature-sensitive defect and GPI2 is essential for vegetative growth (PMID:7768896). Loss of PIGC function reduces or abolishes GPI-GnT activity and produces deficient surface expression of GPI-anchored proteins, established both in PIGC-defective cellular models and in patient-derived leukocytes carrying biallelic disease variants (PMID:27694521, PMID:40962973). Biallelic PIGC mutations cause a severe inherited GPI-deficiency disorder, confirmed across multiple patient cohorts with reduced GPI-AP surface levels (PMID:27694521, PMID:40962973).

1. 1995 High

   Established that the yeast PIGC ortholog GPI2 is genetically required for the first step of GPI biosynthesis and functionally linked to Gpi1, defining the conserved core of the pathway.

   Evidence Temperature-sensitive mutant isolation, gene disruption, in vitro GlcNAc-PI synthesis assay, and overexpression suppression of a gpi1 ts mutant in S. cerevisiae

   PMID:7768896

   Open questions at the time

   • Did not define the molecular composition of the mammalian complex
   • Physical versus purely functional Gpi1-Gpi2 interaction left unresolved in vivo
2. 1996 Medium

   Identified human PIGC as a 297-residue ER membrane protein and the human homologue of yeast GPI2, placing it among the genes required for GlcNAc transfer to PI in mammals.

   Evidence Molecular cloning, sequence homology, membrane fractionation/ER co-localization, and functional complementation

   PMID:8806613

   Open questions at the time

   • Direct biochemical interaction with other PIG subunits not yet demonstrated
   • Catalytic versus accessory role unresolved
3. 1997 Medium

   Mapped PIGC genomic structure and chromosomal location, distinguishing its autosomal genetics from X-linked PIGA and clarifying somatic mutation requirements relevant to PNH.

   Evidence Genomic cloning, FISH chromosomal mapping, and gene structure analysis

   PMID:9325057

   Open questions at the time

   • No functional consequence of the locus tested
   • Pseudogene PIGCP1 role, if any, undefined
4. 1998 High

   Demonstrated that PIGC is a physical subunit of an ER GPI-GnT complex with PIG-A, PIG-H, and hGPI1 that reconstitutes GlcNAc transferase activity and recognizes the PI acyl chains, defining the enzymatic machinery directly.

   Evidence Co-immunoprecipitation of complex components, in vitro GPI-GnT activity assay, and substrate specificity comparison across PI sources

   PMID:9463366

   Open questions at the time

   • Specific catalytic contribution of PIGC versus other subunits not isolated
   • No structural model of the assembled complex
5. 2014 Medium

   Probed species-specific and noncanonical functions of the GPI2 ortholog, including Ras-signaling modulation and a GPI-GnT-independent route to regulating CaERG11, indicating functional divergence beyond the core complex.

   Evidence Cross-species functional complementation, GPI-GnT activity and cell-wall integrity assays, and western blot in S. cerevisiae and C. albicans

   PMID:25117514

   Open questions at the time

   • Relevance of Ras modulation to mammalian PIGC unknown
   • Mechanism of CaGPI19/CaERG11 regulation not resolved
6. 2016 High

   Linked human PIGC missense and nonsense mutations directly to defective GPI anchoring in vivo, establishing PIGC loss-of-function as a cause of reduced GPI-AP surface expression.

   Evidence Transfection of PIGC variants into PIGC-defective mouse cells with flow cytometry, plus patient leukocyte flow cytometry

   PMID:27694521

   Open questions at the time

   • Quantitative effect of each variant on enzyme kinetics not measured
   • Genotype-phenotype correlation across variants not established
7. 2021 Medium

   Characterized the trypanosome ortholog TbGPI2 as a complex subunit whose loss disrupts complex architecture and only partially reduces activity, and revealed an unexpected Golgi localization implicating a noncanonical role.

   Evidence Gene knockout, in vitro GPI-GnT activity assay, co-immunoprecipitation, GPI glycan structural analysis, and immunofluorescence in T. brucei

   PMID:34284059

   Open questions at the time

   • Golgi function not demonstrated for mammalian PIGC
   • Mechanism of residual activity in TbGPI2-null cells unexplained
8. 2021 Low

   Reported a candidate proliferative/cell-cycle role for PIGC in hepatocellular carcinoma cells, raising a possible function beyond GPI anchoring.

   Evidence siRNA knockdown and overexpression in HepG2 and Hcclm3 cells with proliferation, migration, cell-cycle, and cyclin/CDK western blot readouts

   PMID:33854986

   Open questions at the time

   • Single-lab phenotypic study without mechanistic pathway placement
   • Effects not linked to GPI-GnT activity or GPI-AP levels
   • Not independently confirmed
9. 2025 Medium

   Consolidated PIGC as a Mendelian GPI-deficiency gene across an expanded patient cohort, confirming reduced GPI-AP surface levels caused by biallelic variants.

   Evidence Flow cytometry for GPI-AP surface expression in 18 probands and cellular models, with AlphaFold2 structural modelling and exome/genome sequencing

   PMID:40962973

   Open questions at the time

   • Structural predictions not experimentally validated
   • Variant-specific residual enzyme activity not quantified

• Whether PIGC contributes to functions outside the ER GPI-GnT complex—such as the reported Golgi localization, Ras modulation, or cancer cell-cycle roles—remains mechanistically unresolved in mammals.
• No mammalian evidence linking PIGC to non-GPI pathways
• Catalytic versus structural role of PIGC within the GPI-GnT complex not separated
• No experimental structure of the human complex