Alternative titles; symbols
HGNC Approved Gene Symbol: PIGT
Cytogenetic location: 20q13.12 Genomic coordinates (GRCh38) : 20:45,416,141-45,426,241 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.12 | ?Paroxysmal nocturnal hemoglobinuria 2 | 615399 | Autosomal dominant; Somatic mutation | 3 |
| Multiple congenital anomalies-hypotonia-seizures syndrome 3 | 615398 | Autosomal recessive | 3 |
The PIGT gene encodes phosphatidylinositol-glycan biosynthesis class T, a subunit of a heteropentameric transamidase complex that catalyzes the attachment of proteins to glycosylphosphatidylinositol (GPI), which functions as a plasma membrane anchor for extracellular proteins (summary by Ohishi et al., 2001 and Kvarnung et al., 2013).
For information on the PIG gene family and the roles of PIG proteins in GPI biosynthesis, see PIGA (311770).
Ohishi et al. (2001) purified PIGT from the GPI transamidase complex isolated from a human myelogenous leukemia cell line. The full-length PIGT cDNA encodes a deduced 578-amino acid protein with an N-terminal signal peptide and a putative C-terminal transmembrane domain.
Li et al. (2006) cloned mouse Pigt, which they called Ndap. RT-PCR detected expression of Pigt in cortex, cerebellum, spinal cord, heart, liver, intestine, kidney, and muscle, and lower expression in lung and pancreas.
Kvarnung et al. (2013) stated that the PIGT gene contains 12 exons.
Gross (2018) mapped the PIGT gene to chromosome 20q13.12 based on an alignment of the PIGT sequence (GenBank BC015022) with the genomic sequence (GRCh38).
By disruption of the Pigt gene in a mouse embryonal carcinoma cell line, Ohishi et al. (2001) found that Pigt is not required for GPI synthesis but is essential for attachment of GPI to proteins. During the GPI attachment process, GPI transamidase forms a carbonyl intermediate with the precursor protein, and in the absence of Pigt, the carbonyl intermediate was not generated. With the lack of Pigt, the association of Gaa1 (GPAA1; 603048) and Gpi8 (PIGK; 605087) in the GPI complex decreased, whereas the expression of Pigs (610271) remained stable. Coimmunoprecipitation of human GPI complex proteins from transfected CHO cells suggested that PIGT stabilizes GPI8 and GAA1 by binding to them. PIGT also bound to PIGS. Ohishi et al. (2001) concluded that PIGT plays a critical role in the maintenance of the GPI transamidase complex by stabilizing the expression of GAA1 and GPI8 and linking them to PIGS.
By mutation analysis, Ohishi et al. (2003) determined intermolecular disulfide bonds are formed between GPI8 cys92 and PIGT cys182. The disulfide bond was not necessary for the formation of the GPI transamidase complex or for transamidase activity.
Li et al. (2006) found that mouse Pigt expression increased early in the culture of mouse neurons and astrocytes and decreased in older cultures. The expression in older cultures was increased by neurotrophin-3 (162660). Overexpression of fluorescence-tagged Pigt in 4-week-old mouse astrocytes led to the aggregation of Pigt on membrane-bound structures and to apoptotic cell death. By truncation analysis, Vainauskas and Menon (2005) determined that the transmembrane span of PIGT contains an endoplasmic reticulum (ER)-localization signal.
Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 3
In 4 affected members of a consanguineous Turkish family with multiple congenital anomalies-hypotonia-seizures syndrome-3 (MCAHS3; 615398), Kvarnung et al. (2013) identified a homozygous mutation in the PIGT gene (T183P; 610272.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in several large control databases, including 6,500 Exome Sequencing Project exomes and the 1000 Genomes Project, or in 200 Danish exomes. The phenotype was characterized by hypotonia, delayed psychomotor development, seizures, dysmorphic facial features, variable defects of the renal, cardiac, and skeletal systems, and decreased serum alkaline phosphatase.
In a Japanese girl with MCAHS3, Nakashima et al. (2014) identified compound heterozygous mutations in the PIGT gene (610272.0003 and 610272.0004). The mutations were found by whole-exome sequencing and segregated with the disorder in the family.
In 2 brothers with features of MCAHS3, who were born to first-cousin parents of Somali origin, Skauli et al. (2016) identified a homozygous mutation in the PIGT gene (G360V; 610272.0005). The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not seen in the 1000 Genomes Project or ExAC databases or in an in-house database of 443 exomes of mixed ethnicity. The mutation alters a highly conserved amino acid located in the GPI-transamidase domain, which transfers mature GPI anchors to target proteins.
In 2 sibs with MCAHS3, Lam et al. (2015) reported compound heterozygosity for a missense mutation (R488W; 610272.0004) and a frameshift mutation (610272.0006).
Kohashi et al. (2018) reported an 11-month-old boy with acetazolamide-responsive epileptic apnea who presented with decreased serum alkaline phosphatase associated with compound heterozygous PIGT mutations, glu84 to ter (E84X; 610272.0003) and a novel missense variant, gly366 to trp (G366W; 610272.0007).
In 2 sisters with MCAHS3, previously reported by Rauch et al. (1999), Nobrega et al. (2022) identified compound heterozygous mutations in the PIGT gene (610272.0008 and 610272.0009). The mutations were identified by exome sequencing and confirmed by Sanger sequencing.
Paroxysmal Nocturnal Hemoglobinuria 2
In a woman with paroxysmal nocturnal hemoglobinuria-2 (PNH2; 615399), Krawitz et al. (2013) identified a heterozygous germline splice site mutation in the PIGT gene (610272.0002). The mutation, which was found by targeted enrichment of all exons of genes involved in GPI anchor synthesis followed by deep sequencing, was confirmed by Sanger sequencing. Array CGH on patient peripheral cells showed that a large proportion of granulocytes also carried a somatic heterozygous 8-Mb deletion of chromosome 20q11.23-q13.12, including the PIGT gene. Transfection of the splice site mutation into Pigt-null CHO cells caused only a minor increase in CD55 (125240) surface expression but almost no CD59 (107271) expression, suggesting a loss of function. The findings suggested that 2 hits in the PIGT gene, 1 germline and 1 somatic in hematopoietic stem cells, are necessary for development of the disorder.
Kvarnung et al. (2013) found that morpholino knockout of the Pigt ortholog in zebrafish resulted in a dose-dependent increase in abnormal morphant embryos and severity of gastrulation defects, including shortened body axes, longer somites, and broad and kinked notochords.
In 4 affected members of a consanguineous Turkish family with multiple congenital anomalies-hypotonia-seizures syndrome-3 (MCAHS3; 615398), Kvarnung et al. (2013) identified a homozygous c.547A-C transversion in exon 4 of the PIGT gene, resulting in a thr183-to-pro (T183P) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in several large control databases, including 6,500 Exome Sequencing Project exomes and the 1000 Genomes Project, or in 200 Danish exomes. Flow cytometric analysis of patient granulocytes and monocytes showed decreased amounts of GPI-anchored proteins CD16B (610665) and CD59 (107271) compared to controls, indicating that the mutation results in impairment in membrane anchoring of GPI-linked proteins. The T183P variant was unable to rescue gastrulation defects of morpholino-knockout zebrafish, consistent with a defect in enzyme function.
In a woman with paroxysmal nocturnal hemoglobinuria-2 (PNH2; 615399), Krawitz et al. (2013) identified a heterozygous germline A-to-G transition in intron 10 of the PIGT gene (c.1401-2A-G), resulting in the skipping of 84 bp of exon 11 and the deletion of 28 highly conserved amino acids. The mutation, which was found by targeted enrichment of all exons of genes involved in GPI anchor synthesis followed by deep sequencing, was confirmed by Sanger sequencing. Array CGH on patient peripheral cells showed that a large proportion of granulocytes also carried a somatic heterozygous 8-Mb deletion of chromosome 20q11.23-q13.12, including the PIGT gene. Transfection of the splice site mutation into Pigt-null CHO cells caused only a minor increase in CD55 (125240) surface expression but almost no CD59 (107271) expression, suggesting a loss of function.
In a Japanese girl with multiple congenital anomalies-hypotonia-seizures syndrome-3 (MCAHS3; 615398), Nakashima et al. (2014) identified compound heterozygous mutations in the PIGT gene: a c.250G-T transversion (c.250G-T, NM_015937.5) in exon 2, resulting in a glu84-to-ter (E84X) substitution, and a c.1342C-T transition in exon 10, resulting in an arg488-to-trp (R488W; 610272.0004) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and were not found in the 1000 Genomes Project or Exome Sequencing Project databases. The c.1342C-T transition was found in 1 of 408 in-house control exomes. Patient granulocytes showed decreased surface expression of certain GPI-anchored proteins. Transfection of the mutations into PIGT-deficient CHO cells showed that the R488W mutation could partially restore surface expression of GPI-anchored proteins, whereas the E84X mutation resulted in a complete loss of function.
For discussion of the c.1342C-T transition (c.1342C-T, NM_015937.5) in the PIGT gene, resulting in an arg488-to-trp (R488W) substitution, that was found in compound heterozygous state in a patient with multiple congenital anomalies-hypotonia-seizures syndrome-3 (MCAHS3; 615398) by Nakashima et al. (2014), see 610272.0003.
In 2 brothers with multiple congenital anomalies-hypotonia-seizures syndrome-3 (MCAHS3; 615398), who were born to first-cousin parents of Somali origin, Skauli et al. (2016) identified a homozygous mutation in the PIGT gene: a c.1079G-T transversion (c.1079G-T, NM_015937.5), resulting in a gly360-to-val (G360V) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family and was not found in the 1000 Genomes Project or ExAC databases or in an in-house database of 443 exomes of mixed ethnicity. The mutation alters an evolutionary highly conserved amino acid located in the GPI-transamidase domain, which transfers mature GPI anchors to target proteins. In vitro studies in cells from the 2 brothers showed reduced levels of GPI anchors and GPI-anchored proteins on the cell surface.
In 2 sibs with multiple congenital anomalies-hypotonia-seizure syndrome-3 (MCAHS3; 615398) who were born to nonconsanguineous parents of mixed African American and Caucasian ethnic background, Lam et al. (2015) identified compound heterozygosity for a 1-bp duplication in the PIGT gene (c.918dupC, NM_015937.5) and an R488W substitution (610272.0004). The 1-bp duplication results in frameshift and premature termination (Val307ArgfsTer13). The truncated protein was stable but lacking its C-terminal PIGT transmembrane domain, necessary for the function of the GPI anchor protein.
In an 11-month-old Japanese boy with multiple congenital anomalies-hypotonia-seizure syndrome-3 (MCAHS3; 615398), Kohashi et al. (2018) found compound heterozygosity for an E84X mutation (610272.0003) and a c.1096G-T transversion (c.1096G-T, NM_015937.5) resulting in a gly366-to-trp (G366W) substitution.
In 2 sisters with multiple congenital anomalies-hypotonia-seizures syndrome-3 (MCAHS3; 615398), previously reported by Rauch et al. (1999), Nobrega et al. (2022) identified compound heterozygous mutations in the PIGT gene: a c.494-2A-G transition (c.494-2A-G, NM_015937.6) and a c.514C-T transition, resulting in an arg172-to-cys (R172C; 610272.0009) substitution. The mutations were identified by exome sequencing and confirmed by Sanger sequencing.
For discussion of the c.514C-T transition (c.514C-T, NM_015937.6) in the PIGT gene, resulting in an arg172-to-cys (R172C) substitution, that was found in compound heterozygous state in 2 sisters with multiple congenital anomalies-hypotonia-seizures syndrome-3 (MCAHS3; 615898) by Nobrega et al. (2022), see 610272.0008.
Gross, M. B. Personal Communication. Baltimore, Md. 10/22/2018.
Kohashi, K., Ishiyama, A., Yuasa, S., Tanaka, T., Miya, K., Adachi, Y., Sato, N., Saitsu, H., Ohba, C., Matsumoto, N., Murakami, Y., Kinoshita, T., Sugai, K., Sasaki, M. Epileptic apnea in a patient with inherited glycosylphosphatidylinositol anchor deficiency and PIGT mutations. Brain Dev. 40: 53-57, 2018. [PubMed: 28728837] [Full Text: https://doi.org/10.1016/j.braindev.2017.06.005]
Krawitz, P. M., Hochsmann, B., Murakami, Y., Teubner, B., Kruger, U., Klopocki, E., Neitzel, H., Hoellein, A., Schneider, C., Parkhomchuk, D., Hecht, J., Robinson, P. N., Mundlos, S., Kinoshita, T., Schrezenmeier, H. A case of paroxysmal nocturnal hemoglobinuria caused by a germline mutation and a somatic mutation in PIGT. Blood 122: 1312-1315, 2013. [PubMed: 23733340] [Full Text: https://doi.org/10.1182/blood-2013-01-481499]
Kvarnung, M., Nilsson, D., Lindstrand, A., Korenke, G. C., Chiang, S. C. C., Blennow, E., Bergmann, M., Stodberg, T., Makitie, O., Anderlid, B.-M., Bryceson, Y. T., Nordenskjold, M., Nordgren, A. A novel intellectual disability syndrome caused by GPI anchor deficiency due to homozygous mutations in PIGT. J. Med. Genet. 50: 521-528, 2013. [PubMed: 23636107] [Full Text: https://doi.org/10.1136/jmedgenet-2013-101654]
Lam, C., Golas, G. A., Davids, M., Huizing, M., Kane, M. S., Krasnewich, D. M., Malicdan, M. C. V., Adams, D. R., Markello, T. C., Zein, W. M., Gropman, A. L., Lodish, M. B., and 12 others. Expanding the clinical and molecular characteristics of PIGT-CDG, a disorder of glycosylphosphatidylinositol anchors. Molec. Genet. Metab. 115: 128-140, 2015. [PubMed: 25943031] [Full Text: https://doi.org/10.1016/j.ymgme.2015.04.007]
Li, H. L., Li, Z., Qin, L. Y., Liu, S., Lau, L. T., Han, J. S., Yu, A. C. H. The novel neurotrophin-regulated neuronal development-associated protein, NDAP, mediates apoptosis. FEBS Lett. 580: 1723-1728, 2006. [PubMed: 16516892] [Full Text: https://doi.org/10.1016/j.febslet.2006.02.022]
Nakashima, M., Kashii, H., Murakami, Y., Kato, M., Tsurusaki, Y., Miyake, N., Kubota, M., Kinoshita, T., Saitsu, H., Matsumoto, N. Novel compound heterozygous PIGT mutations caused multiple congenital anomalies-hypotonia-seizures syndrome 3. Neurogenetics 15: 193-200, 2014. [PubMed: 24906948] [Full Text: https://doi.org/10.1007/s10048-014-0408-y]
Nobrega, P. R., Castro, M. A. A., de Paiva, A. R. B., Kok, F. Mystery solved after 23 years: M syndrome is PIGT-associated multiple congenital anomalies-hypotonia-seizures syndrome 3. (Letter) Am. J. Med. Genet. 188A: 3567-3568, 2022. [PubMed: 36177944] [Full Text: https://doi.org/10.1002/ajmg.a.62977]
Ohishi, K., Inoue, N., Kinoshita, T. PIG-S and PIG-T, essential for GPI anchor attachment to proteins, form a complex with GAA1 and GPI8. EMBO J. 20: 4088-4098, 2001. [PubMed: 11483512] [Full Text: https://doi.org/10.1093/emboj/20.15.4088]
Ohishi, K., Nagamune, K., Maeda, Y., Kinoshita, T. Two subunits of glycosylphosphatidylinositol transamidase, GPI8 and PIG-T, form a functionally important intermolecular disulfide bridge. J. Biol. Chem. 278: 13959-13967, 2003. [PubMed: 12582175] [Full Text: https://doi.org/10.1074/jbc.M300586200]
Rauch, A., Feindt, K. A., Leonard, C. O., Thompson, J. A., Hoffman, R. O., Creel, D. J., Opitz, J. M. Previously apparently undescribed autosomal recessive MCA-MR syndrome with light fixation, retinal cone dystrophy, and seizures: the M syndrome. Am. J. Med. Genet. 82: 194-198, 1999. [PubMed: 9934988] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19990115)82:2<194::aid-ajmg18>3.0.co;2-7]
Skauli, N., Wallace, S., Chiang, S. C. C., Baroy, T., Holmgren, A., Stray-Pedersen, A., Bryceson, Y. T., Stromme, P., Frengen, E., Misceo, D. Novel PIGT variant in two brothers: expansion of the multiple congenital anomalies-hypotonia seizures syndrome 3 phenotype. Genes (Basel) 7: 108, 2016. Note: Electronic Article. [PubMed: 27916860] [Full Text: https://doi.org/10.3390/genes7120108]
Vainauskas, S., Menon, A. K. Endoplasmic reticulum localization of Gaa1 and PIG-T, subunits of the glycosylphosphatidylinositol transamidase complex. J. Biol. Chem. 280: 16402-16409, 2005. [PubMed: 15713669] [Full Text: https://doi.org/10.1074/jbc.M414253200]