HGNC Approved Gene Symbol: PIGF
Cytogenetic location: 2p21 Genomic coordinates (GRCh38): 2:46,580,937-46,617,041 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p21 | Onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome | 619356 | Autosomal recessive | 3 |
Glycosylphosphatidylinositol (GPI) anchors attach certain proteins to the cell surface membrane. Proteins with appropriate C-terminal signal peptides are transferred to the preformed glycolipid anchor in the endoplasmic reticulum and transported to the cell surface as a single unit. PIGF encodes 1 of the enzymes involved in GPI biosynthesis (Inoue et al., 1993).
For information on the PIG gene family and the roles of PIG proteins in GPI biosynthesis, see PIGA (311770).
By expression cloning to complement deficiency in GPI anchor biosynthesis in the Thy1 (188230)-negative mutant murine thymoma cell line of complementation class F, Inoue et al. (1993) isolated PIGF from a KT-3 human T-cell cDNA library. The deduced 219-amino acid protein lacks a typical N-terminal signal sequence and is more than 55% hydrophobic, suggesting that most of it is embedded in the membrane.
Ohishi et al. (1996) isolated cDNA and genomic clones for Pigf, the murine counterpart of PIGF. They found that Pigf encodes a 219-amino acid protein that complements a class F mutation.
From analysis of PIGF genomic clones, Ohishi et al. (1995) showed that PIGF contains 6 exons spanning about 40 kb.
Ware et al. (1994) showed by interspecific backcross experiments that the Pigf gene in mice maps to chromosome 17. Prediction of the site of the gene in the human was difficult because conserved linkage relationships for that region of the mouse chromosome had not been well characterized.
By fluorescence in situ hybridization (FISH), Ohishi et al. (1995) assigned the PIGF gene to human 2p21-p16. They also identified a processed pseudogene of PIGF and mapped it to 5q35 by FISH.
Hong et al. (2000) found that knockout of Pigf in F9 mouse embryonal carcinoma cells completely eliminated surface expression of Thy1, a protein that requires a GPI anchor for membrane association. In contrast, knockout of Pigo (614730) reduced, but did not eliminate, surface expression of Thy1. Knockout of either Pigo or Pigf resulted in accumulation of the same major GPI intermediate lacking phosphatidylethanolamine (PE) linked to mannose-3 (Man3) of the GPI core, but different minor GPI intermediates. Protein pull-down assays revealed that Pigo and Pigf interacted; however, much of Pigf did not associate with Pigo. Expression of Pigo was much higher in the presence than in the absence of Pigf, whereas Pigf was stable in the absence of Pigo. Hong et al. (2000) concluded that PIGO is involved in, but is not essential for, GPI anchoring of proteins, whereas PIGF is essential for it.
Using Chinese hamster ovary cells deficient in select GPI synthesis proteins, Murakami et al. (2012) found that GPI-anchored proteins were released to the medium following deletion of proteins active in intermediate steps of GPI synthesis, including Pigv (610274), Pigb (604122), and Pigf. Deletion of proteins active earlier in GPI synthesis resulted in degradation of substrate proteins. Similarly, deletion of GPI transamidase subunits, which function late in the process and exchange the substrate protein's GPI signal sequence for the completed GPI anchor, also resulted in degradation of substrate proteins. Substrate proteins released following knockdown of Pigv were cleaved following the GPI signal sequence, but they lacked the GPI anchor. Murakami et al. (2012) concluded that the GPI transamidase can cleave GPI signal sequences on substrate proteins in the presence of an immature GPI anchor with at least 1 mannosyl residue, but that the transamidase requires the mature GPI anchor to complete GPI transfer to substrate proteins.
In the late phase of GPI biosynthesis, the major GPI species, H7, which has ethanolamine phosphate (EtNP) linked to Man3, is generated from the H6 species by an enzyme complex consisting of PIGO and PIGF. Using RNA interference, Shishioh et al. (2005) found that knockdown of GPI7 (PIGG; 616918) caused accumulation of H7 and deficiency of H8 in HeLa cells, suggesting that GPI7 is involved in transfer of EtNP to Man2 on H7 to form H8. Coprecipitation of transfected CHO cells revealed that human PIGF interacted with GPI7 and PIGO in independent complexes. Interaction with PIGF stabilized GPI7 and PIGO, and GPI7 competed with PIGO for binding to PIGF. Overexpression of GPI7 reduced content of PIGO and reduced generation of H7, likely by depletion of available PIGF and destabilization of PIGO. Shishioh et al. (2005) concluded that PIGF and PIGO interact for conversion of H6 to H7, and that PIGF and GPI7 interact for conversion of H7 to H8.
In 2 unrelated children, each born of consanguineous Indian parents, with onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome (OORS; 619356), Salian et al. (2021) identified a homozygous missense mutation in the PIGF gene (P172R; 600153.0001). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. It was not present in the gnomAD database. Flow cytometric analysis of patient cells showed defective GPI anchor biosynthesis that could be restored by expression of wildtype PIGF. Additional functional studies in PIGF-deficient CHO cells showed that the mutant enzyme had low-residual activity compared to wildtype, although levels of the mutant protein were normal. The findings were consistent with PIGF deficiency.
In 2 unrelated children, each born of consanguineous Indian parents, with onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome (OORS; 619356), Salian et al. (2021) identified a homozygous c.515C-G transversion (c.515C-G, NM_173074.3) in the PIGF gene, resulting in a pro172-to-arg (P172R) substitution at a conserved residue in the predicted transmembrane domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in both families. It was not present in the gnomAD database. Flow cytometric analysis of patient cells showed defective GPI anchor biosynthesis that could be restored by expression of wildtype PIGF. Additional functional studies in PIGF-deficient CHO cells showed that the mutant enzyme had low-residual activity compared to wildtype, although levels of the mutant protein were normal.
Hong, Y., Maeda, Y., Watanabe, R., Inoue, N., Ohishi, K., Kinoshita, T. Requirement of PIG-F and PIG-O for transferring phosphoethanolamine to the third mannose in glycosylphosphatidylinositol. J. Biol. Chem. 275: 20911-20919, 2000. [PubMed: 10781593] [Full Text: https://doi.org/10.1074/jbc.M001913200]
Inoue, N., Kinoshita, T., Orii, T., Takeda, J. Cloning of a human gene, PIG-F, a component of glycosyl-phosphatidylinositol anchor biosynthesis, by a novel expression cloning strategy. J. Biol. Chem. 268: 6882-6885, 1993. [PubMed: 8463218]
Murakami, Y., Kanzawa, N., Saito, K., Krawitz, P. M., Mundlos, S., Robinson, P. N., Karadimitris, A., Maeda, Y., Kinoshita, T. Mechanism for release of alkaline phosphatase caused by glycosylphosphatidylinositol deficiency in patients with hyperphosphatasia mental retardation syndrome. J. Biol. Chem. 287: 6318-6325, 2012. [PubMed: 22228761] [Full Text: https://doi.org/10.1074/jbc.M111.331090]
Ohishi, K., Inoue, N., Endo, Y., Fujita, T., Takeda, J., Kinoshita, T. Structure and chromosomal localization of the GPI-anchor synthesis gene PIGF and its pseudogene psi-PIGF. Genomics 29: 804-807, 1995. [PubMed: 8575782] [Full Text: https://doi.org/10.1006/geno.1995.9929]
Ohishi, K., Kurimoto, Y., Inoue, N., Endo, Y., Takeda, J., Kinoshita, T. Cloning and characterization of the murine GPI anchor synthesis gene Pigf, a homologue of the human PIGF gene. Genomics 34: 340-346, 1996. [PubMed: 8786134] [Full Text: https://doi.org/10.1006/geno.1996.0296]
Salian, S., Benkerroum, H., Nguyen, T. T. M., Nampoothiri, S., Kinoshita, T., Felix, T. M., Stewart, F., Sisodiya, S. M., Murakami, Y., Campeau, P. M. PIGF deficiency causes a phenotype overlapping with DOORS syndrome. Hum. Genet. 140: 879-884, 2021. [PubMed: 33386993] [Full Text: https://doi.org/10.1007/s00439-020-02251-2]
Shishioh, N., Hong, Y., Ohishi, K., Ashida, H., Maeda, Y., Kinoshita, T. GPI7 is the second partner of PIG-F and involved in modification of glycosylphosphatidylinositol. J. Biol. Chem. 280: 9728-9734, 2005. [PubMed: 15632136] [Full Text: https://doi.org/10.1074/jbc.M413755200]
Ware, R. E., Howard, T. A., Kamitani, T., Chang, H.-M., Yeh, E. T. H., Seldin, M. F. Chromosomal assignment of genes involved in glycosylphosphatidylinositol anchor biosynthesis: implications for the pathogenesis of paroxysmal nocturnal hemoglobinuria. Blood 83: 3753-3757, 1994. [PubMed: 8204896]