HGNC Approved Gene Symbol: PIGQ
Cytogenetic location: 16p13.3 Genomic coordinates (GRCh38) : 16:569,968-584,109 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.3 | Multiple congenital anomalies-hypotonia-seizures syndrome 4 | 618548 | Autosomal recessive | 3 |
Many eukaryotic proteins are anchored to the membrane through the hydrocarbon chains of a covalently bound glycosylphosphatidylinositol (GPI) membrane anchor. GPI anchoring is important for regulation of cell growth and activation. GPI biosynthesis in the endoplasmic reticulum (ER) is initiated by transfer of N-acetylglucosamine (GlcNAc) from UDP-GlcNAc to phosphatidylinositol (PI). This transfer is catalyzed by GlcNAc transferase (GPI-GnT) and enzyme activity requires several genes, including PIGQ (summary by Tiede et al., 1998).
For information on the PIG gene family and the roles of PIG proteins in GPI biosynthesis, see PIGA (311770).
In a database search for homologs of yeast Gpi1, Tiede et al. (1998) and Watanabe et al. (1998) identified PIGQ, which they called hGPI1. The full-length PIGQ cDNA encodes a deduced 581-amino acid protein that shares 24% overall amino acid identity with yeast Gpi1. The C-terminal half of PIGQ is better conserved than the N-terminal half. Watanabe et al. (1998) predicted that PIGQ has several hydrophobic regions, some of which may be transmembrane domains, and a potential tyrosine phosphorylation site in the third cytoplasmic loop. Tiede et al. (1998) predicted that most of the amino acids and conserved residues are on the cytoplasmic face of the ER and that there are no significant domains in the lumen of the ER. Tiede et al. (1998) and Hong et al. (1999) independently cloned the mouse PIGQ homolog, which shares 85 to 89% amino acid identity with human PIGQ.
Using immunoprecipitation experiments, Watanabe et al. (1998) demonstrated that PIGQ associates specifically with PIGA, PIGC (601730), and PIGH (600154) and that all 4 proteins form a complex that has GPI-GnT activity in vitro. The authors concluded that these 4 proteins form part or all of GPI-GnT.
By expressing the mouse and human PIGQ in Gpi1-deficient S. cerevisiae, Tiede et al. (1998) demonstrated that PIGQ specifically rescues S. cerevisiae Gpi1 mutants, indicating that mouse and human PIGQ are indeed orthologs of yeast Gpi1 and that there is a high degree of evolutionary conservation in GPI biosynthesis. Tiede et al. (1998) concluded that PIGQ is involved in the first step of GPI biosynthesis and that the specific function of PIGQ may be to stabilize the enzyme complex in the ER rather than to participate in catalysis of GlcNAc transfer.
By comparing cDNA and genomic sequence, Hong et al. (1999) predicted that PIGQ is encoded by 11 exons.
Using fluorescence in situ hybridization, Hong et al. (1999) mapped the PIGQ gene to chromosome 16p13.3.
In a child of West African descent with multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4; 618548), Martin et al. (2014) identified a homozygous splice site mutation in the PIGQ gene (605754.0001). The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation occurred before the catalytic domain of PIGQ, suggesting that it abrogated the function of the enzyme and led to a reduction in GPI synthesis. Transfection of the mutation into PIGQ-deficient CHO cells did not restore GPI-anchored protein expression as efficiently as wildtype, and expression of the mutant protein was decreased compared to wildtype, consistent with a loss-of-function effect.
In a patient (12DG0223) with MCAHS4, Alazami et al. (2015) identified a homozygous nonsense mutation in the PIGQ gene (R207X; 605754.0002). The patient was part of a large cohort of 143 multiplex consanguineous families with various neurodevelopmental disorders who underwent whole-exome sequencing. Functional studies of the PIGQ variant and studies of patient cells were not performed.
In a male infant with MCAHS4, Starr et al. (2019) identified compound heterozygous mutations in the PIGQ gene (605765.0003 and 605754.0004). The mutations, which were found by whole-exome sequencing, were each inherited from an unaffected parent, confirming segregation within the family. Functional studies of the variants and studies of patient cells were not performed, but the variants were predicted to have a loss-of-function effect.
In 7 patients from 6 families with MCAHS4, Johnstone et al. (2020) identified 8 different mutations in the PIGQ gene (see, e.g., 605754.0004-605754.0006), 7 of which were novel, in homozygous or compound heterozygous state. The mutations were identified by whole-exome sequencing. In blood from 2 patients (St4 and St5), flow cytometry revealed low levels of FLAER and CD16 (see 146740) cell surface localization. Markers of GPI-anchored proteins measured by flow cytometry were decreased in fibroblasts from patients St3b and St5. Transduction with a lentivirus containing wildtype PIGQ completely restored GPI-anchored protein expression in fibroblasts from patient St3b and partially restored the expression in fibroblasts from patient St5.
Hong et al. (1999) disrupted the mouse Gpi1 gene in F9 embryonal carcinoma cells, which caused a severe but not complete defect in the generation of GPI-anchored proteins. A complex of Piga, Pigh, and Pigc decreased to a nearly undetectable level, whereas a complex of Piga and Pigh was easily detected. A lack of Gpi1 also caused partial decreases of Pigc and Pigh. Therefore, GPI1 stabilizes the enzyme by tying up Pigc with a complex of Piga and Pigh.
In a child of West African descent with multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4; 618548), Martin et al. (2014) identified a homozygous A-to-G transition in intron 2 of the PIGQ gene (c.690-2A-G, NM_004204), resulting in the skipping of exon 3 and an in-frame deletion of 44 amino acids. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation occurred before the catalytic domain of PIGQ, suggesting that it abrogated the function of the enzyme and led to a reduction in GPI synthesis. Transfection of the mutation into PIGQ-deficient CHO cells did not restore GPI-anchored protein expression as efficiently as wildtype, and expression of the mutant protein was decreased compared to wildtype, consistent with a loss-of-function effect. The patient had onset of seizures at 4 weeks of age.
In a patient (12DG0223) with multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4; 618548), Alazami et al. (2015) identified a homozygous c.619C-T transition (c.619C-T, NM_004204.2) in the PIGQ gene, resulting in an arg207-to-ter (R207X) substitution. The patient was part of a large cohort of 143 multiplex consanguineous families with various neurodevelopmental disorders who underwent whole-exome sequencing. Functional studies of the PIGQ variant and studies of patient cells were not performed.
In a male infant with multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4; 618548), Starr et al. (2019) identified compound heterozygous mutations in the PIGQ gene: a 2-bp deletion (c.968_969delTG), predicted to result in a frameshift and premature termination (Leu323ProfsTer119), and an in-frame 3-bp deletion (c.1199_1201delACT; 605754.0004), predicted to result in the deletion of conserved residue Tyr400 (Y400del). The mutations, which were found by whole-exome sequencing, were each inherited from an unaffected parent, confirming segregation within the family. The Y400del mutation was found at a low frequency (0.02%) in the ExAC database. Functional studies of the variants and studies of patient cells were not performed, but the variants were predicted to have a loss-of-function effect. The patient had onset of refractory seizures around 7 months of age and died at 10 months.
For discussion of the in-frame 3-bp deletion (c.1199_1201delACT) in the PIGQ gene, predicted to result in the deletion of conserved residue Tyr400 (Y400del), that was found in compound heterozygous state in a patient with multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4; 618548) by Starr et al. (2019), see 605754.0004.
In female sibs (patients St3a and St3b) with MCAHS4, Johnstone et al. (2020) identified compound heterozygous mutations in the PIGQ gene: Y400del and a 2-bp deletion (c.1578_1579del; 605754.0005) predicted to result in a frameshift and premature termination (Gln527AlafsTer75). The mutations were identified by whole-exome sequencing. Each parent was heterozygous for one of the mutations. Flow cytometry in fibroblasts from patient St3b showed decreased FLAER and decreased CD73 (129190) and CD109 (608859) GPI-anchored proteins. Transduction with a lentivirus containing wildtype PIGQ restored GPI-anchored protein expression.
In a patient (patient St2) with MCAHS4, Johnstone et al. (2020) identified compound heterozygous mutations in the PIGQ gene: Y400del and a c.942+1G-A mutation in intron 4 (IVS4+1G-A; 605754.0006), predicted to disrupt a canonical splice site. The mutations were identified by whole-exome sequencing. Each parent was heterozygous for one of the mutations. Flow cytometry in fibroblasts from the patient showed decreased CD59 (107271) expression.
For discussion of the 2-bp deletion (c.1578_1579del, NM_004204.3) in the PIGQ gene, resulting in a frameshift and premature termination (Gln527AlafsTer75), that was found in compound heterozygous state in sibs with multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4; 618548) by Johnstone et al. (2020), see 605754.0004.
For discussion of the IVS4+1G-A mutation (c.942+1G-A, NM_004204.3) in the PIGQ gene that was found in compound heterozygous state in a patient with multiple congenital anomalies-hypotonia-seizures syndrome-4 (MCAHS4; 618548) by Johnstone et al. (2020), see 605754.0004.
Alazami, A. M., Patel, N., Shamseldin, H. E., Anazi, S., Al-Dosari, M. S., Alzahrani, F., Hijazi, H., Alshammari, M., Aldahmesh, M. A., Salih, M. A., Faqeih, E., Alhashem, A., and 41 others. Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Cell Rep. 10: 148-161, 2015. [PubMed: 25558065] [Full Text: https://doi.org/10.1016/j.celrep.2014.12.015]
Hong, Y., Ohishi, K., Watanabe, R., Endo, Y., Maeda, Y., Kinoshita, T. GPI1 stabilizes an enzyme essential in the first step of glycosylphosphatidylinositol biosynthesis. J. Biol. Chem. 274: 18582-18588, 1999. [PubMed: 10373468] [Full Text: https://doi.org/10.1074/jbc.274.26.18582]
Johnstone, D. L., Nguyen, T. T. M., Zambonin, J., Kernohan, K. D., St-Denis, A., Baratang, N. V., Hartley, T., Geraghty, M. T., Richer, J., Majewski, J., Bareke, E., Guerin, A., and 12 others. Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ: report of seven new subjects and review of the literature. J. Inherit. Metab. Dis. 43: 1321-1332, 2020. Note: Erratum: J. Inherit. Metab. Dis. 46: 156 only, 2023. [PubMed: 32588908] [Full Text: https://doi.org/10.1002/jimd.12278]
Martin, H. C., Kim, G. E., Pagnamenta, A. T., Murakami, Y., Carvill, G. L., Meyer, E., Copley, R. R., Rimmer, A., Barcia, G., Fleming, M. R., Kronengold, J., Brown, M. R., and 21 others. Clinical whole-genome sequencing in severe early-onset epilepsy reveals new genes and improves molecular diagnosis. Hum. Molec. Genet. 23: 3200-3211, 2014. [PubMed: 24463883] [Full Text: https://doi.org/10.1093/hmg/ddu030]
Starr, L. J., Spranger, J. W., Rao, V. K., Lutz, R., Yetman, A. T. PIGQ glycosylphosphatidylinositol-anchored protein deficiency: characterizing the phenotype. Am. J. Med. Genet. 179A: 1270-1275, 2019. [PubMed: 31148362] [Full Text: https://doi.org/10.1002/ajmg.a.61185]
Tiede, A., Schubert, J., Nischan, C., Jensen, I., Westfall, B., Taron, C. H., Orlean, P., Schmidt, R. E. Human and mouse Gpi1p homologues restore glycosylphosphatidylinositol membrane anchor biosynthesis in yeast mutants. Biochem. J. 334: 609-616, 1998. [PubMed: 9729469] [Full Text: https://doi.org/10.1042/bj3340609]
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]