Alternative titles; symbols
HGNC Approved Gene Symbol: PIGC
Cytogenetic location: 1q24.3 Genomic coordinates (GRCh38): 1:172,441,457-172,444,069 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q24.3 | Glycosylphosphatidylinositol biosynthesis defect 16 | 617816 | Autosomal recessive | 3 |
Many eukaryotic membrane proteins are anchored to membranes via glycosylphosphatidylinositol (GPI) anchors. GPI anchoring is a posttranslational modification occurring in the endoplasmic reticulum (ER). The PIGC gene encodes an ER membrane protein required for the first step of GPI biosynthesis (Inoue et al., 1996).
For information on the PIG gene family and the roles of PIG proteins in GPI biosynthesis, see PIGA (311770).
Inoue et al. (1996) cloned PIGC, a human homolog of yeast Gpi2. PIGC encodes a 297-amino acid polypeptide that is 20% identical to yeast Gpi2. Using immunolocalization, they found human PIGC protein to be present primarily in the ER in transfected cells.
Inoue et al. (1996) found that transfection of human PIGC into human cells mutant for PIGC activity restored proper GPI anchoring.
Using immunoprecipitation experiments, Watanabe et al. (1998) demonstrated that PIGQ (605754) associates specifically with PIGA, PIGC, and PIGH (600154) and that all 4 proteins form a complex that has GPI-GlcNAc transferase (GPI-GnT) activity in vitro.
Hong et al. (1997) mapped the PIGC gene to chromosome 1q23-q25 by fluorescence in situ hybridization. they also mapped an intronless pseudogene, PIGCP1, to chromosome 11p13-p12. The presence of a processed pseudogene is a feature common to PIGA, PIGF (600153), and PIGC.
In 3 patients from 2 unrelated families with glycosylphosphatidylinositol biosynthesis defect-16 (GPIBD16; 617816), Edvardson et al. (2017) identified homozygous or compound heterozygous mutations in the PIGC gene (601730.0001-601730.0003). The mutations, which were found by exome analysis, segregated with the disorder in both families. Flow cytometric analysis of patient leukocytes showed variably decreased expression of GPI-anchored proteins, including CD16 (FCGR3A; 146740) and CD55 (125240). Transfection of the mutations into PIGC-null cells showed that the mutations were unable to rescue cell surface expression of GPI-anchored proteins, consistent with a partial or almost complete loss-of-function effect.
In 2 sibs, born of consanguineous Arab parents (family A), with glycosylphosphatidylinositol biosynthesis defect-16 (GPIBD16; 617816), Edvardson et al. (2017) identified a homozygous c.566T-G transversion (c.566T-G, NM_153747) in the PIGC gene, resulting in a leu189-to-trp (L189W) substitution at a highly conserved residue. The mutation, which was found by exome analysis, segregated with the disorder in the family and was not found in the ExAC database or in an in-house database of about 800 exomes. Transfection of the mutation into PIGC-null cells showed that it was unable to fully rescue cell surface expression of GPI-anchored proteins, consistent with a partial loss-of-function effect.
In a patient, born of unrelated parents (family B), with glycosylphosphatidylinositol biosynthesis defect-16 (GPIBD16; 617816), Edvardson et al. (2017) identified compound heterozygous mutations in the PICG gene: a c.61C-T transition (61C-T, NM_153747), resulting in an arg21-to-ter (R21X) substitution, and a c.635T-C transition resulting in a leu212-to-pro (L212P; 601730.0003) substitution at a highly conserved residue. The mutations, which were found by exome analysis, segregated with the disorder in the family. The L212P variant was not found in the ExAC database, but R21X was carried by 16 of 60,700 individuals in the ExAC database. Transfection of the mutations into PIGC-null cells showed that they were unable to fully rescue cell surface expression of GPI-anchored proteins, consistent with a partial or almost complete loss-of-function effect.
For discussion of the c.635T-C transition (c.635T-C, NM_153747) in the PIGC gene, resulting in a leu212-to-pro (L212P) substitution, that was found in compound heterozygous state in a patient with glycosylphosphatidylinositol biosynthesis defect-16 (GPIBD16; 617816) by Edvardson et al. (2017), see 601730.0002.
Edvardson, S., Murakami, Y., Nguyen, T. T. M., Shahrour, M., St-Denis, A., Shaag, A., Damseh, N., Le Deist, F., Bryceson, Y., Abu-Libdeh, B., Campeau, P. M., Kinoshita, T., Elpeleg, O. Mutations in the phosphatidylinositol glycan C (PIGC) gene are associated with epilepsy and intellectual disability. J. Med. Genet. 54: 196-201, 2017. [PubMed: 27694521] [Full Text: https://doi.org/10.1136/jmedgenet-2016-104202]
Hong, Y., Ohishi, K., Inoue, N., Endo, Y., Fujita, T., Takeda, J., Kinoshita, T. Structures and chromosomal localizations of the glycosylphosphatidylinositol synthesis gene PIGC and its pseudogene PIGCP1. Genomics 44: 347-349, 1997. [PubMed: 9325057] [Full Text: https://doi.org/10.1006/geno.1997.4893]
Inoue, N., Watanabe, R., Takeda, J., Kinoshita, T. PIG-C, one of the three human genes involved in the first step of glycosylphosphatidylinositol biosynthesis is a homologue of Saccharomyces cerevisiae GPI2. Biochem. Biophys. Res. Commun. 226: 193-199, 1996. [PubMed: 8806613] [Full Text: https://doi.org/10.1006/bbrc.1996.1332]
Watanabe, R., Inoue, N., Westfall, B., Taron, C. H., Orlean, P., Takeda, J., Kinoshita, T. The first step of glycosylphosphatidylinositol biosynthesis is mediated by a complex of PIG-A, PIG-H, PIG-C and GPI1. EMBO J. 17: 877-885, 1998. [PubMed: 9463366] [Full Text: https://doi.org/10.1093/emboj/17.4.877]