HGNC Approved Gene Symbol: PIGO
Cytogenetic location: 9p13.3 Genomic coordinates (GRCh38) : 9:35,088,688-35,096,591 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9p13.3 | Hyperphosphatasia with impaired intellectual development syndrome 2 | 614749 | Autosomal recessive | 3 |
Many proteins are anchored to cell surface membranes via a glycosylphosphatidylinositol (GPI) modification. PIGO is involved GPI biosynthesis in the endoplasmic reticulum (ER) and has a role in the transfer of phosphatidylethanolamine (PE) to the third mannose (Man3) of the GPI core (Hong et al., 2000).
For information on the PIG gene family and the roles of PIG proteins in GPI biosynthesis, see PIGA (311770).
Hong et al. (2000) cloned mouse Pigo from a testis cDNA library, and they identified human PIGO by database analysis. The deduced 1,101-amino acid mouse protein has a transmembrane domain near the N terminus, followed by a hydrophilic region of about 400 amino acids and 15 transmembrane domains in the C-terminal half. The hydrophilic region contains motifs conserved in various phosphodiesterases and nucleotide pyrophosphatases. Pigo also has 2 potential N-glycosylation sites. Western blot analysis of transfected and fractionated CHO cells revealed that Pigo associated with ER membrane markers.
Hong et al. (2000) determined that the PIGO gene contains 10 exons.
Hong et al. (2000) reported that the PIGO gene maps to chromosome 9p13.
Hong et al. (2000) found that knockout of Pigo in F9 mouse embryonal carcinoma cells reduced, but did not eliminate, surface expression of Thy1 (188230), a protein that requires a GPI anchor for membrane association. In contrast, knockout of Pigf (600153) completely eliminated surface expression of Thy1. Knockout of either Pigo or Pigf resulted in accumulation of the same major GPI intermediate lacking PE on Man3, 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 not essential for, GPI anchoring of proteins, whereas PIGF is essential for it. They hypothesized that PIGF may have other partners for transferring PE onto Man3, possibly resulting in a minor change in GPI structure.
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.
By exome sequencing of 2 sisters with hyperphosphatasia with impaired intellectual development syndrome-2 (HPMRS2; 614749), Krawitz et al. (2012) identified compound heterozygosity for 2 mutations in the PIGO gene (614730.0001 and 614730.0002). Sequencing of this gene in 11 additional patients with a similar disorder identified 1 patient who was compound heterozygous for 2 mutations (614730.0001 and 614730.0003). In vitro functional expression studies showed that the mutant proteins either lacked or had decreased functional activity. PIGO-deficient CHO cell lines had decreased cell surface placental alkaline phosphatase (ALP) activity with increased secretion of ALP, which was rescued by transfection with wildtype PIGO. The findings indicated that hyperphosphatasia in the patients with PIGO mutations is a result of release of ALP into the serum due to a defect in GPI anchoring of ALP to the cell membrane.
In 2 sisters, born of unrelated British parents, with hyperphosphatasia with impaired intellectual development syndrome-2 (HPMRS2; 614749), Krawitz et al. (2012) identified compound heterozygosity for 2 mutations in the PIGO gene: a 2869C-T transition resulting in a leu957-to-phe (L957F) substitution, and a 1-bp duplication (2361dupC; 614730.0002), resulting in a frameshift and premature termination (Thr788HisfsTer5). The mutations were detected by whole-exome sequencing and confirmed by Sanger sequencing. The L957F substitution occurs in a highly conserved residue in the transmembrane domain. Each unaffected parent was heterozygous for 1 of the mutations. Sequencing of the PIGO gene in 11 additional patients with a similar phenotype identified compound heterozygous mutations in 1 patient: L957F and a G-to-A transition in intron 8 (3069+5G-A; 614730.0003), resulting in the skipping of exon 9. The splice site mutation was found in 1 of 5,379 controls. In vitro functional expression studies demonstrated that the 2361dupC mutation did not result in restoration of CD59 (107271) expression at the cell surface of PIGO-deficient CHO cells, and that L957F induced only low levels of CD59 expression in these cells. The mutant truncated protein was expressed at high levels compared to wildtype, whereas the L957F protein was expressed at decreased levels. PIGO-deficient CHO cell lines had decreased cell surface placental alkaline phosphatase (ALP) activity with increased secretion of ALP, which was rescued by transfection with wildtype PIGO. The findings indicated that hyperphosphatasia in the patients with PIGO mutations is a result of release of ALP into the serum due to a defect in glycosylphosphatidylinositol (GPI) anchoring of ALP to the cell membrane.
For discussion of the 1-bp duplication in the PIGO gene (2361dupC) that was found in compound heterozygous state in 2 sisters with hyperphosphatasia with impaired intellectual development syndrome-2 (HPMRS2; 614749) by Krawitz et al. (2012), see 614730.0001.
For discussion of the splice site mutation in the PIGO gene (3069+5G-A) that was found in compound heterozygous state in 2 sisters with hyperphosphatasia with impaired intellectual development syndrome-2 (HPMRS2; 614749) by Krawitz et al. (2012), see 614730.0001.
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]
Krawitz, P. M., Murakami, Y., Hecht, J., Kruger, U., Holder, S. E., Mortier, G. R., Delle Chiaie, B., De Baere, E., Thompson, M. D., Roscioli, T., Kielbasa, S., Kinoshita, T., Mundlos, S., Robinson, P. N., Horn, D. Mutations in PIGO, a member of the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation. Am. J. Hum. Genet. 91: 146-151, 2012. [PubMed: 22683086] [Full Text: https://doi.org/10.1016/j.ajhg.2012.05.004]
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]