HGNC Approved Gene Symbol: PIGH
Cytogenetic location: 14q24.1 Genomic coordinates (GRCh38): 14:67,589,306-67,600,301 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q24.1 | Glycosylphosphatidylinositol biosynthesis defect 17 | 618010 | Autosomal recessive | 3 |
The PIGH gene encodes an enzyme involved in the biosynthesis of glycosylphosphatidylinositol (GPI) anchor (Kamitani et al., 1993).
For information on the PIG gene family and the roles of PIG proteins in GPI biosynthesis, see PIGA (311770).
Kamitani et al. (1993) isolated cDNA for a human gene that repaired the defect in a complementation class H mutant cell line. They determined that PIGH encodes a predicted protein of 188 amino acids.
Gross (2018) mapped the PIGH gene to chromosome 14q24.1 based on an alignment of the PIGH sequence (GenBank BC004100) with the genomic sequence (GRCh38).
Ware et al. (1994) demonstrated that the mouse Pigh gene is located on chromosome 12 in a region of homology of synteny with human 14q11-q24.
Watanabe et al. (1996) demonstrated that the PIGA and PIGH proteins form a protein complex and are subunits of the GPI GlcNAc transferase of the endoplasmic reticulum (ER). They showed that PIGH is a cytoplasmic ER-associated protein.
Using immunoprecipitation experiments, Watanabe et al. (1998) demonstrated that PIGQ (605754) associates specifically with PIGA, PIGC (601730), and PIGH and that all 4 proteins form a complex that has GPI-GlcNAc transferase (GPI-GnT) activity in vitro.
In 2 sibs, born of consanguineous Pakistani parents, with glycosylphosphatidylinositol biosynthesis defect-17 (GPIBD17; 618010), Pagnamenta et al. (2018) identified a homozygous mutation in the start codon of the PIGH gene (M1L; 600154.0001). The proband was part of a cohort of 7,833 parent-child trios and 1,792 singleton patients from the Deciphering Developmental Disorders (DDD) study who underwent targeted sequencing of genes involved in the GPI pathway. The mutation was confirmed by Sanger sequencing and segregated with the disorder in the family. Transfection of the mutation into PIGH-deficient CHO cells showed that mutant PIGH was unable to efficiently restore the surface expression of GPI-anchored proteins. The authors postulated that the mutation resulted in some residual activity.
In a 5-year-old boy, born of consanguineous Indian parents, with GPIBD17, Nguyen et al. (2018) identified a homozygous missense mutation in the PIGH gene (S103P; 600154.0002). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed, but patient granulocytes showed about 50% decreased cell surface expression of CD16 (see 146740) and decreased cell surface expression of CD55 (125240), consistent with a defect in GPI-anchored proteins and suggesting a loss of function.
In 4 patients, including a sib pair, from 3 families with GPIBD17, Tremblay-Laganiere et al. (2021) identified homozygous missense mutations in the PIGH gene (S103P, 600154.0002; R163W; 600154.0003).
In a patient, born to consanguineous parents, with GPIBD17, do Rosario et al. (2022) identified homozygosity for the R163W mutation in the PIGH gene (600154.0003). The mutation, which was identified by whole-exome sequencing, segregated with the disorder in the family.
In 2 sibs (proband Decipher ID 265247), born of consanguineous Pakistani parents, with glycosylphosphatidylinositol biosynthesis defect-17 (GPIBD17; 618010), Pagnamenta et al. (2018) identified a homozygous c.1A-T transversion (c.1A-T, NM_004569.3) in the start codon of the PIGH gene, predicted to result in a met1-to-leu (M1L) substitution. The mutation, which was found by targeted sequencing of PIG-related genes and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was found in the gnomAD database at a low frequency (0.002%) in heterozygous state only; it was not found in the 1000 Genomes Project database. Transfection of the mutation into PIGH-deficient CHO cells showed that mutant PIGH was unable to efficiently restore the surface expression of GPI-anchored proteins. Western blot analysis showed that the variant resulted in a truncated version of PIGH, consistent with use of an alternative in-frame start site in exon 2. The authors postulated that the mutation resulted in some residual activity.
In a 5-year-old boy, born of consanguineous Indian parents, with glycosylphosphatidylinositol biosynthesis defect-17 (GPIBD17; 618010), Nguyen et al. (2018) identified a homozygous c.307T-C transition (c.307T-C, NM_004569.3) in the PIGH gene, resulting in a ser103-to-pro (S103P) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was found at a low frequency (0.00001625, with 4 heterozygotes) in the gnomAD database. Functional studies of the variant were not performed, but patient granulocytes showed about 50% decreased cell surface expression of CD16 (see 146740) and decreased cell surface expression of CD55 (125240), consistent with a defect in GPI-anchored proteins and suggesting a loss of function.
Tremblay-Laganiere et al. (2021) identified homozygosity for the S104P mutation in the PIGH gene in 2 unrelated patients (patients 1 and 3) with GPIBD17. Patient 3 was born to consanguineous Azerbaijani parents. The variant, which was identified by whole-exome sequencing in patient 1, was present in the gnomAD database at an allele frequency of 0.0000159. Levels of CD16 were decreased in granulocytes from patient 1.
In 2 Guatemalan sibs (patients 2A and 2B), born to unrelated parents, with glycosylphosphatidylinositol biosynthesis defect-17 (GPIBD17; 618010), Tremblay-Laganiere et al. (2021) identified homozygosity for a c.487C-T transition (c.487C-T, NM_004569) in the PIGH gene, resulting in an arg163-to-trp (R163W) substitution at a conserved residue near the C-terminal end of the protein. Both patients had delayed myelination on brain MRI.
In a patient, born to consanguineous parents, with GPIBD17, do Rosario et al. (2022) identified homozygosity for the R163W substitution at a conserved residue in the PIGH protein. The mutation was identified by trio whole-exome sequencing and segregated with disorder in the family. The mutation was present in only heterozygous state in the gnomAD database at an allele frequency of 0.00002658. Functional studies were not performed. The patient had delayed myelination on brain MRI.
do Rosario, M. C., Kaur, P., Girisha, K. M., Bielas, S., Shukla, A. Homozygous variant p.(Arg163Trp) in PIGH causes glycosylphosphatidylinositol biosynthesis defect with epileptic encephalopathy and delayed myelination. Clin. Dysmorph. 31: 196-200, 2022. [PubMed: 35445667] [Full Text: https://doi.org/10.1097/MCD.0000000000000423]
Gross, M. B. Personal Communication. Baltimore, Md. 7/10/2018.
Kamitani, T., Chang, H.-M., Rollins, C., Waneck, G. L., Yeh, E. T. H. Correction of the class A defect in glycosylphosphatidylinositol anchor biosynthesis in Ltk-cells by human cDNA clone. J. Biol. Chem. 268: 20733-20736, 1993. [PubMed: 8407896]
Nguyen, T. T. M., Mahida, S., Smith-Hicks, C., Campeau, P. M. A PIGH mutation leading to GPI deficiency is associated with developmental delay and autism. Hum. Mutat. 39: 827-829, 2018. [PubMed: 29603516] [Full Text: https://doi.org/10.1002/humu.23426]
Pagnamenta, A. T., Murakami, Y., Anzilotti, C., Titheradge, H., Oates, A. J., Morton, J., the DDD Study, Kinoshita, T., Kini, U., Taylor, J. C. A homozygous variant disrupting the PIGH start-codon is associated with developmental delay, epilepsy, and microcephaly. Hum. Mutat. 39: 822-826, 2018. [PubMed: 29573052] [Full Text: https://doi.org/10.1002/humu.23420]
Tremblay-Laganiere, C., Kaiyrzhanov, R., Maroofian, R., Nguyen, T. T. M., Salayev, K., Chilton, I. T., Chung, W. K., Madden, J. A., Phornphutkul, C., Agrawal, P. B., Houlden, H., Campeau, P. M. PIGH deficiency can be associated with severe neurodevelopmental and skeletal manifestations. Clin. Genet. 99: 313-317, 2021. [PubMed: 33156547] [Full Text: https://doi.org/10.1111/cge.13877]
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]
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]
Watanabe, R., Kinoshita, T., Masaki, R., Yamamoto, A., Takeda, J., Inoue, N. PIG-A and PIG-H, which participate in glycosylphosphatidylinositol anchor biosynthesis, form a protein complex in the endoplasmic reticulum. J. Biol. Chem. 271: 26868-26875, 1996. [PubMed: 8900170] [Full Text: https://doi.org/10.1074/jbc.271.43.26868]