HGNC Approved Gene Symbol: PIGW
Cytogenetic location: 17q12 Genomic coordinates (GRCh38) : 17:36,534,987-36,539,303 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q12 | Glycosylphosphatidylinositol biosynthesis defect 11 | 616025 | Autosomal recessive | 3 |
Glycosylphosphatidylinositol (GPI) is a complex glycolipid that anchors many proteins to the cell surface. PIGW acts in the third step of GPI biosynthesis and acylates the inositol ring of phosphatidylinositol (Murakami et al., 2003).
For information on the PIG gene family and the roles of PIG proteins in GPI biosynthesis, see PIGA (311770).
By database searching for sequences similar to rat Pigw, Murakami et al. (2003) identified human PIGW. The deduced 504-amino acid protein contains 13 transmembrane domains and shares 77% sequence identity with the rat protein. Fractionation of a human lymphoblastoid cell line revealed that PIGW associated with the endoplasmic reticulum (ER). Murakami et al. (2003) determined that the N terminus and several conserved regions of rat Pigw face the lumen of the ER, whereas its C terminus is cytoplasmic.
Murakami et al. (2003) demonstrated that rat Pigw has inositol acyltransferase activity, generating N-acetylglucosamine-acylphosphatidylinositol (GlcN-acylPI).
Murakami et al. (2003) determined that PIGW is an intronless gene.
By genomic sequence analysis, Murakami et al. (2003) mapped the PIGW gene to chromosome 17q.
In a Japanese boy, born of unrelated parents, with glycosylphosphatidylinositol biosynthesis defect-11 (GPIBD11; 616025), Chiyonobu et al. (2014) identified compound heterozygous missense mutations in the PIGW gene: T71P (610275.0001) and M167V (610275.0002). In vitro functional expression studies suggested that the mutations reduced PIGW activity. However, Chiyonobu et al. (2014) noted that confirmation of the findings in additional families was warranted.
In 2 second-degree cousins with GPIBD11, Hogrebe et al. (2016) identified a homozygous missense mutation in the PIGW gene (R154G; 610375.0003). The mutation was found by next generation sequencing and confirmed by Sanger sequencing. Transfection of rat Pigw carrying the R154G mutation into Pigw-deficient CHO cells failed to restore surface expression of certain GPI-anchored proteins, indicating that it is a hypomorphic allele. The patients did not have increased serum alkaline phosphatase, but did have subtle deficiencies in the cellular expression of certain GPI-anchored protein, particularly CD16 (see 146740).
By whole-exome sequencing in a cohort of 19 families with a history of fetal anomalies, Meier et al. (2019) identified a homozygous missense mutation in the PIGW gene (R36G; 610275.0004) in 2 sib fetuses (family 9).
In a Chinese boy, born of unrelated parents, with GPIBD11, Fu et al. (2019) identified compound heterozygous missense mutations in the PIGW gene (D60N, 610275.0005 and R154S, 610275.0006). The mutations were found by trio whole-exome sequencing.
In an Egyptian girl, born to consanguineous parents, with GPIBD11, Peron et al. (2020) identified a homozygous missense mutation in the PIGW gene (L26S; 610275.0007). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in public variant databases.
In a Japanese boy, born of unrelated parents, with glycosylphosphatidylinositol biosynthesis defect-11 (GPIBD11; 616025), Chiyonobu et al. (2014) identified compound heterozygous mutations in the PIGW gene: a c.211A-C transversion, resulting in a thr71-to-pro (T71P) substitution in the second transmembrane domain, and a c.499A-G transition, resulting in a met167-to-val (M167V; 610275.0002) substitution in the fifth transmembrane domain. Both mutations occurred at highly conserved residues. The mutations were found by targeted sequencing of known GPI-anchor synthesis genes after the patient was found to have elevated serum alkaline phosphatase (ALP). Transfection of the mutations into PIGW-deficient CHO cells showed that the T71P mutant only partially restored, and M167V did not restore at all, the surface expression of GPI-anchored protein (GPI-AP) using a weak promoter. The expression of the T71P mutant protein was one-third that of wildtype, whereas M167V expression was similar to wildtype. The findings suggested that the mutations caused hypomorphic alleles.
For discussion of the met167-to-val (M167V) mutation in the PIGW gene that was found in compound heterozygous state in a patient with glycosylphosphatidylinositol biosynthesis defect-11 (GPIBD11; 616025), by Chiyonobu et al. (2014), see 610275.0001.
In 2 second-degree cousins with glycosylphosphatidylinositol biosynthesis defect-11 (GPIBD11; 616025), Hogrebe et al. (2016) identified a homozygous c.460A-G transition (c.460A-G, NM_178517.3) in the PIGW gene, resulting in an arg154-to-gly (R154G) substitution at a highly conserved residue. The mutation was found by next-generation sequencing and confirmed by Sanger sequencing. Transfection of rat Pigw carrying the R154G mutation into Pigw-deficient CHO cells failed to restore surface expression of certain GPI-anchored proteins, indicating that it is a hypomorphic allele. The patients did not have increased serum alkaline phosphatase, but did have subtle deficiencies in the cellular expression of certain GPI-anchored protein, particularly CD16.
In 2 sib fetuses (family 9) with glycosylphosphatidylinositol biosynthesis defect-11 (GPIBD11; 616025), Meier et al. (2019) identified a homozygous c.106A-G transition (c.106A-G, NM_178517.3) in the PIGW gene, resulting in an arg36-to-gly (R36G) substitution in the transmembrane domain. The mutation, which was identified by whole-exome sequencing, was present in the gnomAD database at an allele frequency of 0.0002. The mutation was likely pathogenic according to ACMG guidelines.
In a Chinese boy with glycosylphosphatidylinositol biosynthesis defect-11 (GPIBD11; 616025), Fu et al. (2019) identified compound heterozygous mutations in exon 2 of the PIGW gene: a c.178G-A transition, resulting in an asp60-to-asn (D60N) substitution, and a c.462A-T transversion, resulting in an arg154-to-ser (R154S) substitution. The mutations were identified by trio whole-exome sequencing and confirmed by Sanger sequencing; each parent carried one of the mutations in heterozygous state. A similarly affected sib had died at 7 months of age, but molecular studies were not performed. Functional studies were not performed.
For discussion of the c.462A-T transversion in the PIGW gene, resulting in an arg154-to-ser (R154S) substitution, that was identified in compound heterozygous state in a Chinese patient with glycosylphosphatidylinositol biosynthesis defect-11 (GPIBD11; 616025) by Fu et al. (2019), see 610275.0006.
In an Egyptian girl, born to consanguineous parents, with glycosylphosphatidylinositol biosynthesis defect-11 (GPIBD11; 616025), Peron et al. (2020) identified a homozygous c.77T-C transition (c.77T-C, NM_178517.4) in the PIGW gene, resulting in a leu26-to-ser (L26S) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in the parents. The mutation was not present in the gnomAD database.
Chiyonobu, T., Inoue, N., Morimoto, M., Kinoshita, T., Murakami, Y. Glycosylphosphatidylinositol (GPI) anchor deficiency caused by mutations in PIGW is associated with West syndrome and hyperphosphatasia with mental retardation syndrome. J. Med. Genet. 51: 203-207, 2014. [PubMed: 24367057] [Full Text: https://doi.org/10.1136/jmedgenet-2013-102156]
Fu, L., Liu, Y., Chen, Y., Yuan, Y., Wei, W. Mutations in the PIGW gene associated with hyperphosphatasia and mental retardation syndrome: a case report. BMC Pediat 19: 68, 2019. [PubMed: 30813920] [Full Text: https://doi.org/10.1186/s12887-019-1440-8]
Hogrebe, M., Murakami, Y., Wild, M., Ahlmann, M., Biskup, S., Hortnagel, K., Gruneberg, M., Reunert, J., Linden, T., Kinoshita, T., Marquardt, T. A novel mutation in PIGW causes glycosylphosphatidylinositol deficiency without hyperphosphatasia. Am. J. Med. Genet. 170A: 3319-3322, 2016. [PubMed: 27626616] [Full Text: https://doi.org/10.1002/ajmg.a.37950]
Meier, N., Bruder, E., Lapaire, O., Hoesli, I., Kang, A., Hench, J., Hoeller, S., De Geyter, J., Miny, P., Heinimann, K., Chaoui, R., Tercanli, S., Filges, I. Exome sequencing of fetal anomaly syndromes: novel phenotype-genotype discoveries. Europ. J. Hum. Genet. 27: 730-737, 2019. [PubMed: 30679815] [Full Text: https://doi.org/10.1038/s41431-018-0324-y]
Murakami, Y., Siripanyapinyo, U., Hong, Y., Kang, J. Y., Ishihara, S., Nakakuma, H., Maeda, Y., Kinoshita, T. PIG-W is critical for inositol acylation but not for flipping of glycosylphosphatidylinositol-anchor. Molec. Biol. Cell 14: 4285-4295, 2003. [PubMed: 14517336] [Full Text: https://doi.org/10.1091/mbc.e03-03-0193]
Peron, A., Iascone, M., Salvatici, E., Cavirani, B., Marchetti, D., Corno, S., Vignoli, A. PIGW-related glycosylphosphatidylinositol deficiency: Description of a new patient and review of the literature. Am. J. Med. Genet. 182A: 1477-1482, 2020. [PubMed: 32198969] [Full Text: https://doi.org/10.1002/ajmg.a.61555]